USE OF MUTATIONAL SIGNATURES FOR MULTIPLE CANCER TYPES

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the filing date of U.S. application No. 63/176,562, filed on Apr. 19, 2021, the disclosure of which is incorporated by reference herein.

BACKGROUND

Somatic mutations that arise in solid tumors are currently understood to be predominantly a consequence of genomic instability, evoked by a handful of established driver mutations. In contrast with this random mutagenesis that accompanies tumor progression, investigators have also identified a small proportion that constitute regular patterns of mutation occurrence. Such distinct, reoccurring changes in the tumor genome have been recognized as signatures or “fingerprints” of exposure to specific environmental mutagens, endogenous processes, or defective DNA repair (Alexandrov et al., 2020; Alexandrov et al., 2013; Alexandrov et al., 2014). Mutational signatures have been identified and validated via experimental carcinogenesis in cancer cell and stem cell lines, yeast, and other model systems (Koh et al., 2020). Oncogenic mechanisms as well as exposures implicated in etiology have been highlighted by the specific mutational processes identified.

While mechanistic and etiologic understanding has been enhanced by mutational signature identification, signatures have seldom been evaluated in relation to clinical outcomes. Individuals with DNA repair defects, in particular, have had altered outcomes following chemotherapy in several studies (Gryfe et al., 2000; Ribic et al., 2003). In one recent investigation, women with triple-negative breast tumors, for instance, were more likely to harbor homologous repair defects in tumors, and responded more favorably to chemotherapy (Staaf et al., 2019). Such findings suggest that signatures of DNA repair deficiency and other mutational processes may have unrealized clinical utility.

SUMMARY

As disclosed herein single base substitution signatures, covering a range of environmental agent and endogenous exposures, as well as defective DNA repair pathways, were identified that were associated with cancer survival. Algorithms for mutational signature assessment were applied to elucidate cancer-specific outcomes.

In particular, sixteen cancers met inclusion criteria for in-depth analysis, although information on 33 total cancers is included. Of the 49 signatures, 36 were associated with DSS in at least one cancer. Most common signatures influencing survival included a clock-like signature associated with age in six cancers, deregulated APOBEC-related cytosine deamination in five, and defective DNA repair also in five. Patients with signatures of tobacco exposure had increased risks of cancer-specific mortality in breast (4-fold), low grade glioma (2.2 to 2.8-fold), and skin cutaneous melanoma (3-fold). Some signatures related to DSS were also implicated in stage III/IV disease (Table 2). Addition of mutational signatures increased the c-index in all cancers. After signature inclusion, tumor mutational burden (TMB) did not add further significant prognostic discrimination. Mutational signatures may influence clinical outcomes. Signatures not previously linked to DSS may shed light on metastasis-related mechanisms, and may allow for improved understanding of poor prognosis tumors.

Other combinations of signatures may be employed to in methods for determining disease-free interval, progression-free interval survival, progression-free survival or overall survival in a patient.

The methods may be employed to select patients who should begin therapy sooner, may benefit from a specific therapy or may delay therapy, e.g., chemotherapy, radiotherapy or other immune therapies such as checkpoint inhibitor therapy.

In one embodiment, the patient has Adrenocortical carcinoma (ACC), Bladder Urothelial Carcinoma (BLCA), Bladder Urothelial Carcinoma (BLCA), Brain Lower Grade Glioma (LGG), Breast invasive carcinoma (BRCA), Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), Cholangiocarcinoma (CHOL), Colon adenocarcinoma (COAD), Esophageal carcinoma (ESCA), Glioblastoma multiforme (GBM), Head and Neck squamous cell carcinoma (HNSC), Kidney Chromophobe (KICH), Kidney renal clear cell carcinoma (KIRC), Kidney renal papillary cell carcinoma (KIRP), Liver hepatocellular carcinoma (LIHC), Lung adenocarcinoma (LUAD), Lung squamous cell carcinoma (LUSC), Lymphoid Neoplasm Diffuse Large B-cell b Lymphoma (DLBC), Mesothelioma (MESO), Ovarian serous cystadenocarcinoma (OV), Pancreatic adenocarcinoma (PAAD), Pheochromocytoma and Paraganglioma (PCPG), Prostate adenocarcinoma (PRAD), Rectum adenocarcinoma (READ), Sarcoma (SARC), Skin Cutaneous Melanoma (SKCM), Stomach adenocarcinoma (STAD), Testicular Germ Cell Tumors (TGCT), Thymoma (THYM), Thyroid carcinoma (THCA), Uterine Carcinosarcoma (UCS), or Uterine Corpus Endometrial Carcinoma (UCEC).

The use of the identified signatures may be employed to direct therapy, e.g., the signatures may identify an individual that will benefit from one therapy over another, identify an individual that is responding well to a therapy or identify an individual where therapy should be discontinued, e.g., replaced with another therapy, in specific cancers as not every signature is associated with all cancers examined. Moreover, the use of the signatures may identify an individual who should be aggressively treated versus an individual where watchful waiting or hospice is indicated.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1a-1g. Relationship between disease-specific survival (DSS) and endogenous signature as represented by: a) Clock-like age (SBS1); b) APOBEC (SBS2); c) Mismatch repair deficiency (SBS6); d) Polymerase epsilon defects (SBS10b); e) APOBEC (SBS13); f) Mismatch repair deficiency (SBS26); g) base excision repair deficiency (SBS30). Endogenous processes with more than one SBS signature are labeled with that signature number.

FIGS. 2a-2d. Survival plots for a) BLCA and SBS2, b) BRCA and SBS15, c) HNSC and SBS85, d) LGG and SBS30] Legend FIG. 2: Time-to-event for endogenous processes related to disease-specific survival (DSS): a) APOBEC in BLCA, b) Mismatch repair in BRCA; c) Activation-induced cytosine deaminase in HNSC; d) Base excision repair in LGG.

FIGS. 3a-3g. Relationship between disease-specific survival (DSS) and exogenous mutagen signature as represented by: a) Ultraviolet (SBS7a); b) Ultraviolet (SBS7b); c) Ultraviolet (SBS7c); d) Aristolochic acid (SBS22); e) Aflatoxin (SBS24); f) Chemotherapy (SBS25); g) Platinum chemotherapy (SB31). Exogenous mutagens with more than one signature are labeled with that signature number.

FIGS. 4a-4d. Survival plots for a) BLCA and SBS22, b) COAD and SBS18, c) LGG and SBS4, d) SKCM and SBS7a] Legend FIG. 4: Time-to-event for exogenous mutagens related to disease-specific survival (DSS): a) Aristolochic acid in BLCA, b) Reactive oxygen species in COAD; c) Tobacco (SBS4) in LGG; d) Ultraviolet in SKCM.

DETAILED DESCRIPTION

A method to determine disease-specific, disease-free interval, progression-free, progression-free interval, and/or overall survival in a cancer patient is provided. In one embodiment, the method includes obtaining a tumor sample from a patient with, for example, breast cancer (BRCA), bladder cancer (BLCA), colon adenocarcinoma (COAD), brain lower grade glioma (LGG), liver hepatocellular carcinoma (LIHC), ovarian serous cystadenocarcinoma (OV), stomach adenocarcinoma (STAD), uterine corpus endometrial carcinoma (UCEC), skin cutaneous melanoma (SKC), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), head and neck squamous cell carcinoma (HNSC), lung squamous cell carcinoma (LUSC) or pancreatic adenocarcinoma (PAAD); and determining if the tumor sample has one or more mutational signatures comprising one or more of the mutational signatures in Table 2, or any combination thereof, wherein the presence of the one or more signatures in Table 2 in the sample relative to a corresponding sample without the one or more signatures in Table 2 is indicative of disease-specific survival in the patient. In one embodiment, the one or more signatures are selected from SBS1, SBS2, SBS6, SBS10a, SBS10b, SBS13, SBS15, SBS20, SBS26, or SBS30, or any combination thereof. In one embodiment, the cancer is COAD, LGG, LIHC, OV, STAD, or UCEC. In one embodiment, the cancer is BRCA, COAD, LIHC, or STAD. In one embodiment, the cancer is BLCA, BRCA, LGG, SKC or STAD. In one embodiment, the cancer is LIHC or HNSC. In one embodiment, the sample is from a stage I cancer. In one embodiment, the sample is from a stage III/IV cancer. In one embodiment, one of the mutational signatures in Table 2 is detected. In one embodiment, two or more of the mutational signatures in Table 2 are detected. In one embodiment, up to thirteen of the mutational signatures in Table 2 are detected. In one embodiment, the presence of SBS1 is detected. In one embodiment, the presence of SBS2 or SBS13, or both, is detected. In one embodiment, the presence of SBS6, 15, 20, or 26, or any combination, is detected. In one embodiment, the presence of SBS30 is detected. In one embodiment, the presence of SBS10a or SBS10b, or both, is detected. In one embodiment, the presence of the one or more mutational signatures is indicative of increased survival. In one embodiment, the presence of the one or more mutational signatures is indicative of decreased survival. In one embodiment, the one or more mutational signatures are detected using a nucleic acid amplification reaction. In one embodiment, the one or more mutational signatures are detected using a probe. In one embodiment, the one or more mutational signatures are detected using sequencing. In one embodiment, the presence of the one or more mutational signatures is indicative of response to therapy. In one embodiment, the presence of the one or more mutational signatures is indicative of a need for therapy, e.g., due to increased risk of disease-specific mortality. In one embodiment, the therapy is radiotherapy. In one embodiment, the therapy is chemotherapy. In one embodiment, the therapy is immunotherapy. In one embodiment, the therapy is antibody therapy.

An algorithm that detects mutational signatures correlated with disease-specific survival is disclosed in Blokzijl et al. (2018), which is incorporated by reference herein. The method includes detecting in a tumor sample from a cancer patient whole exome, whole genome, or targeted sequence(s), the presence of one or more mutational signatures comprising one or more of the mutational signatures in Table 2, or any combination thereof, wherein the presence of the one or more signatures in Table 2 in the sample relative to a corresponding sample without the one or more signatures in Table 2 is indicative of altered disease-specific or disease-free survival in the patient.

The method includes detecting in a tumor sample whole exome, whole genome, or targeted sequence from a cancer patient the presence of one or more mutational signatures comprising one or more of the mutational signatures in Table 2, wherein the presence of the one or more signatures in Table 2 in the sample relative to a corresponding sample without the one or more signatures in Table 2 is indicative of altered overall survival in the patient.

The method includes detecting in a tumor sample, e.g., via whole exome, whole genome, targeted or other methods of detecting a sequence in a tumor sample, from a cancer patient the presence of one or more mutational signatures comprising one or more of the mutational signatures in Table 2, wherein the presence of the one or more signatures in Table 2 in the sample relative to a corresponding sample without the one or more signatures in Table 2 is indicative of altered progression-free survival in the patient

The method includes detecting in a tumor sample whole exome, whole genome, or targeted sequence from a cancer patient the presence of one or more mutational signatures comprising one or more of the mutational signatures in Table 2, wherein the presence of the one or more signatures in Table 2 in the sample relative to a corresponding sample without the one or more signatures in Table 2 is indicative of altered progression-free interval survival in the patient.

In one embodiment, the one or more signatures are selected from SBS1, SBS2, SBS6, SBS10a, SBS10b, SBS13, SBS15, SBS20, SBS26, or SBS30, or any combination thereof. In one embodiment, the cancer is COAD, LGG, LIHC, OV, STAD, or UCEC. In one embodiment, the cancer is BRCA, COAD, LIHC, or STAD. In one embodiment, the cancer is BLCA, BRCA, LGG, SKC or STAD. In one embodiment, the cancer is LIHC or HNSC. In one embodiment, the sample is from a stage I or stage II cancer. In one embodiment, the sample is from a stage III/IV cancer. In one embodiment, one of the mutational signatures in Table 2 is detected. In one embodiment, two or more of the mutational signatures in Table 2 are detected. In one embodiment, up to thirteen of the mutational signatures in Table 2 are detected. In one embodiment, the presence of SBS1 is detected. In one embodiment, the presence of SBS2 or SBS13, or both, is detected. In one embodiment, the presence of SBS6, 15, 20, or 26, or any combination, is detected. In one embodiment, the presence of SBS30 is detected. In one embodiment, the presence of SBS10a or SBS10b, or both, is detected. In one embodiment, the presence of the one or more mutational signatures is indicative of increased survival. In one embodiment, the presence of the one or more mutational signatures is indicative of decreased survival. In one embodiment, the one or more mutational signatures are detected using a nucleic acid amplification reaction. In one embodiment, the one or more mutational signatures are detected using a probe. In one embodiment, the one or more mutational signatures are detected using sequencing. In one embodiment, the presence of the one or more mutational signatures is indicative of response to therapy. In one embodiment, the presence of the one or more mutational signatures is indicative of a need for therapy, e.g., due to increased risk of disease-specific mortality. In one embodiment, the therapy is radiotherapy. In one embodiment, the therapy is chemotherapy. In one embodiment, the therapy is immunotherapy. In one embodiment, the therapy is antibody therapy. In one embodiment, the therapy is targeted therapy.

A method to determine disease-specific survival in a cancer patient is provided. The method includes obtaining a tumor sample from a patient with any cancer and determining if the tumor sample has one or more mutational signatures comprising one or more of the mutational signatures in Table 2, or any combination thereof, wherein the presence of the one or more signatures in Table 2 in the sample relative to a corresponding sample without the one or more signatures in Table 2 is indicative of altered disease-specific, progression-free, disease-free, or overall survival in the patient. In one embodiment, the one or more signatures are selected from SBS1, SBS2, SBS6, SBS10a, SBS10b, SBS13, SBS15, SBS20, SBS26, or SBS30, or any combination thereof. In one embodiment, the cancer is COAD, LGG, LIHC, OV, STAD, or UCEC. In one embodiment, the cancer is BRCA, COAD, LIHC, or STAD. In one embodiment, the cancer is BLCA, BRCA, LGG, SKC or STAD. In one embodiment, the cancer is LIHC or HNSC. In one embodiment, the sample is from a stage I cancer. In one embodiment, the sample is from a stage III/IV cancer. In one embodiment, one of the mutational signatures in Table 2 is detected. In one embodiment, two or more of the mutational signatures in Table 2 are detected. In one embodiment, up to thirteen of the mutational signatures in Table 2 are detected. In one embodiment, the presence of SBS1 is detected. In one embodiment, the presence of SBS2 or SBS13, or both, is detected. In one embodiment, the presence of SBS6, 15, 20, or 26, or any combination, is detected. In one embodiment, the presence of SBS30 is detected. In one embodiment, the presence of SBS10a or SBS10b, or both, is detected. In one embodiment, the presence of the one or more mutational signatures is indicative of increased survival. In one embodiment, the presence of the one or more mutational signatures is indicative of decreased survival. In one embodiment, the one or more mutational signatures are detected using a nucleic acid amplification reaction. In one embodiment, the one or more mutational signatures are detected using a probe. In one embodiment, the one or more mutational signatures are detected using sequencing. In one embodiment, the presence of the one or more mutational signatures is indicative of response to therapy. In one embodiment, the presence of the one or more mutational signatures is indicative of a need for therapy, e.g., due to increased risk of disease-specific mortality. In one embodiment, the therapy is radiotherapy. In one embodiment, the therapy is chemotherapy. In one embodiment, the therapy is immunotherapy. In one embodiment, the therapy is antibody therapy. The term “anticancer agent” or “additional anticancer agent” (depending on the context of its use) shall mean chemotherapeutic agents such as an agent selected from the group consisting of microtubule-stabilizing agents, microtubule-disruptor agents, alkylating agents, antimetabolites, epidophyllotoxins, antineoplastic enzymes, topoisomerase inhibitors, inhibitors of cell cycle progression, and platinum coordination complexes. These may be selected from the group consisting of everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1 modulator, a Bcl-2 inhibitor, an HDAC inhbitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an EGFR TK inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, a PI3 kinase inhibitors, an AKT inhibitor, a JAK/STAT inhibitor, a checkpoint-1 or 2 inhibitor, a focal adhesion kinase inhibitor, a Map kinase kinase (mek) inhibitor, a VEGF trap antibody, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR₁ KRX-0402, lucanthone, LY 317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5′-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]-benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258,); 3-[5-(methylsulfonylpiperadinemethyl)-indolyl]-quinolone, vatalanib, AG-013736, AVE-0005, the acetate salt of [D-Ser(Bu t) 6, Azgly 10] (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t)-Leu-Arg-Pro-Azgly-NH₂ acetate [C₅₉H₈₄N₁₈Oi₄-(C₂H₄O₂)x where x=1 to 2.4], goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, lonafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosine arabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortezimib, paclitaxel, cremophor-free paclitaxel, docetaxel, epithilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787/ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zolendronate, prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2, megestrol, immune globulin, nitrogen mustard, methylprednisolone, ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, an NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa and darbepoetin alfa, among others. In one embodiment, the therapy includes administration of a checkpoint inhibitor. In one embodiment, the inhibitor comprises pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, or ipilimumab.

EXEMPLARY EMBODIMENTS

A method to detect mutational signatures correlated with disease-specific survival is provided. The method includes detecting in a tumor sample from a cancer patient the presence of one or more mutational signatures comprising one or more of the mutational signatures in Table 2, wherein the presence of the one or more signatures in Table 2 in the sample relative to a corresponding sample without the one or more signatures in Table 2 is indicative of disease-specific survival in the patient. In one embodiment, the one or more signatures are selected from SBS1, SBS2, SBS6, SBS10a, SBS10b, SBS13, SBS15, SBS20, SBS26, or SBS30, or any combination thereof. In one embodiment, the cancer is COAD, LGG, LIHC, OV, STAD, or UCEC. In one embodiment, the cancer is BRCA, COAD, LIHC, or STAD. In one embodiment, the cancer is BLCA, BRCA, LGG, SKC or STAD. In one embodiment, the cancer is LIHC or HNSC. In one embodiment, the sample is from a stage I cancer. In one embodiment, the sample is from a stage II/III/IV cancer. In one embodiment, one of the mutational signatures in Table 2 is detected. In one embodiment, two or more of the mutational signatures in Table 2 are detected. In one embodiment, up to thirteen of the mutational signatures in Table 2 are detected. In one embodiment, the presence of SBS1 is detected. In one embodiment, the presence of SBS2 or SBS13, or both, is detected. In one embodiment, the presence of SBS6, 15, 20, or 26, or any combination, is detected. In one embodiment, the presence of SBS30 is detected. In one embodiment, the presence of SBS10a or SBS10b, or both, is detected. In one embodiment, the presence of the one or more mutational signatures is indicative of increased survival. In one embodiment, the presence of the one or more mutational signatures is indicative of decreased survival. In one embodiment, the one or more mutational signatures are detected using a nucleic acid amplification reaction. In one embodiment, the one or more mutational signatures are detected using a probe. In one embodiment, the one or more mutational signatures are detected using sequencing. In one embodiment, the sequencing is specific for the one or more mutational signatures. In one embodiment, the presence of the one or more mutational signatures is indicative of response to therapy. In one embodiment, the presence of the one or more mutational signatures is indicative of a need for therapy. In one embodiment, the therapy is radiotherapy. In one embodiment, the therapy is chemotherapy. In one embodiment, the therapy is immunotherapy. In one embodiment, the therapy is antibody therapy.

Also provided is a method to determine disease-specific survival in a cancer patient, including obtaining a tumor sample from a patient with breast cancer (BRCA), bladder cancer (BLCA), colon adenocarcinoma (COAD), brain lower grade glioma (LGG), liver hepatocellular carcinoma (LIHC), ovarian serous cystadenocarcinoma (OV), stomach adenocarcinoma (STAD), uterine corpus endometrial carcinoma (UCEC), skin cutaneous melanoma (SKC), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), head and neck squamous cell carcinoma (HNSC), lung squamous cell carcinoma (LUSC) or pancreatic adenocarcinoma (PAAD); and determining if the tumor sample has one or more mutational signatures comprising one or more of the mutational signatures in Table 2, wherein the presence of the one or more signatures in Table 2 in the sample relative to a corresponding sample without the one or more signatures in Table 2 is indicative of disease-specific survival in the patient. In one embodiment, the one or more signatures are selected from SBS1, SBS2, SBS6, SBS10a, SBS10b, SBS13, SBS15, SBS20, SBS26, or SBS30, or any combination thereof. In one embodiment, the cancer is COAD, LGG, LIHC, OV, STAD, or UCEC. In one embodiment, the cancer is BRCA, COAD, LIHC, or STAD. In one embodiment, the cancer is BLCA, BRCA, LGG, SKC or STAD. In one embodiment, the cancer is LIHC or HNSC. In one embodiment, the sample is from a stage I cancer. In one embodiment, the sample is from a stage II/III/IV cancer. In one embodiment, one of the mutational signatures in Table 2 is detected. In one embodiment, two or more of the mutational signatures in Table 2 are detected. In one embodiment, up to thirteen of the mutational signatures in Table 2 are detected. In one embodiment, the presence of SBS1 is detected. In one embodiment, the presence of SBS2 or SBS13, or both, is detected. In one embodiment, the presence of SBS6, 15, 20, or 26, or any combination, is detected. In one embodiment, the presence of SBS30 is detected. In one embodiment, the presence of SBS10a or SBS10b, or both, is detected. In one embodiment, the presence of the one or more mutational signatures is indicative of increased survival. In one embodiment, the presence of the one or more mutational signatures is indicative of decreased survival. In one embodiment, the one or more mutational signatures are detected using a nucleic acid amplification reaction. In one embodiment, the one or more mutational signatures are detected using a probe. In one embodiment, the one or more mutational signatures are detected using sequencing. In one embodiment, the sequencing is specific for the one or more mutational signatures. In one embodiment, the presence of the one or more mutational signatures is indicative of response to therapy. In one embodiment, the presence of the one or more mutational signatures is indicative of a need for therapy. In one embodiment, the therapy is radiotherapy. In one embodiment, the therapy is chemotherapy. In one embodiment, the therapy is immunotherapy. In one embodiment, the therapy is antibody therapy.

Also provided is a method to detect mutational signatures correlated with disease-specific survival, disease-free interval, progression-free interval, progression-free survival or overall survival, comprising:

• • detecting in a tumor sample from a cancer patient the presence of one or more mutational signatures comprising one or more of the mutational signatures in Table 2, or any combination thereof, wherein the presence of the one or more signatures in Table 2 in the sample relative to a corresponding sample without the one or more signatures in Table 2, is indicative of disease-specific survival, disease-free interval, progression-free interval, progression-free survival or overall survival in the patient. In one embodiment, the presence of the one or more mutational signatures is indicative of response to therapy. In one embodiment, the presence of the one or more mutational signatures is indicative of a need for therapy. In one embodiment, the therapy is radiotherapy. In one embodiment, the therapy is chemotherapy. In one embodiment, the therapy is immunotherapy. In one embodiment, the therapy is antibody therapy.

A kit is provided comprising one or more primers or one or more probes specific for detecting the one or more of the mutational signatures in Table 2.

A microarray is provided comprising one or more probes specific for detecting the one or more of the mutational signatures in Table 2.

Further provided is a method to treat cancer in a human, comprising: administering an anti-cancer therapy to a human having a tumor comprising one or more of the mutational signatures in Table 2 that is/are indicative of decreased disease-specific survival, shorter disease-free interval, shorter progression-free interval, shorter progression-free survival or decreased overall survival. In one embodiment, the human has breast cancer (BRCA), bladder cancer (BLCA), colon adenocarcinoma (COAD), brain lower grade glioma (LGG), liver hepatocellular carcinoma (LIHC), ovarian serous cystadenocarcinoma (OV), stomach adenocarcinoma (STAD), uterine corpus endometrial carcinoma (UCEC), skin cutaneous melanoma (SKC), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), head and neck squamous cell carcinoma (HNSC), lung squamous cell carcinoma (LUSC) or pancreatic adenocarcinoma (PAAD). In one embodiment, the one or more signatures are selected from SBS1, SBS2, SBS6, SBS10a, SBS10b, SBS13, SBS15, SBS20, SBS26, or SBS30, or any combination thereof. In one embodiment, the therapy is radiotherapy. In one embodiment, the therapy is chemotherapy. In one embodiment, the therapy is immunotherapy. In one embodiment, the therapy is antibody therapy. In one embodiment, the presence of the one or more mutational signatures is detected using a probe, sequencing or nucleic acid amplification, or a combination thereof.

The invention will be described by the following non-limiting examples.

Example 1

Mutational signatures, which act as fingerprints of exogenous or endogenous DNA damage, have been associated with cancer incidence, but their influence on cancer outcomes is less clear. It was determined whether single base substitution signatures influenced disease-specific survival (DSS). Exome sequencing data from The Cancer Genome Atlas was utilized. Inclusion was restricted to tumors with at least 50 DSS events. Standard algorithms for mutational signature assessment were applied, and tumor mutational burden (TMB) was evaluated. Cox proportional hazard survival models were fit with adjustment for clinical factors, and hazard ratios and 95% confidence intervals (CI) were calculated. Improvement in model fit with addition of signatures and TMB was quantified using the concordance index (c-index).

Methods

Tumor exome sequencing data were derived from The Cancer Genome Atlas (TCGA) (Weinstein et al., 2013). Description of cancer patient recruitment, follow-up, and ascertainment of disease outcomes has been published previously (Liu et al., 2018). TCGA somatic mutation data of 10,179 patients (reference genome GRCh38) from 33 cancer types were downloaded from the Genomic Data Commons. Eligible cancers for in-depth analysis were those with at least 50 disease-specific survival (DSS) events, and only TCGA participants with DSS outcomes that were deemed appropriately defined (Liu et al., 2018) were retained. FIGS. 7-16 include data from all 33 cancers, all 49 signatures, and the following measures of survival: overall survival, disease-free interval, disease-specific survival, progression-free survival, and progression-free interval. Stage 0 cancers were also omitted, and those missing stage were excluded from stage-specific analyses. The cancer type abbreviations, full name, and detailed sample size are available in Table 1 and below. The probability matrix for 49 established COSMIC reference mutational signatures (v3) was downloaded from Synapse Documentation (https://www.synapse.org/#ISynapse:syn11738319)).

Signature Identification

The association of mutational signatures with endogenous processes or exogenous mutagens has been described in several publications (Alexandrov et al., 2020; Alexandrov et al., 2013; Alexandrov et al., 2014; Gerstung et al., 2020; Catalogue of Somatic Mutations in Cancer (https://cancer.sanger.ac.uk/cosmic). A catalog of 96 three-nucleotide motifs that surround the mutational focus (one upstream nucleotide+mutation site+one downstream nucleotide site), and derived frequency tables of this motif catalog for each involved patient, was formalized. A computational function from R package MutationalPatterns (Blokzijl et al., 2018) was leveraged to fit the patient mutational motif frequency tables to the reference mutational signatures while requiring the coefficients, i.e., signature-to-patient contribution strengths, be non-negative values. The estimated coefficients came out in the form of a 96-by-10,179 matrix of non-negative values.

Statistical Analysis

Disease-specific survival (DSS) was one outcome of interest. Thus, disease-specific mortality was counted as an event, and deaths from other causes (competing risks) and loss-to-follow up were censored. Time to event (cancer, other cause of death, or end of follow-up period) was calculated by TCGA as days from cancer diagnosis. To correct for disease-free immortal person-time, which is present in the time from diagnosis to recruitment, disease-specific survival time was recalculated. Time from diagnosis to recruitment was incorporated into statistical models as immortal person-time. Mutational signatures were modeled in relationship to survival as continuous or discrete (excluding zero) measures, and also using a single cutpoint determined by maximally selected rank statistics (Hothorn, 2003), employing a restriction that the cutpoint include cell sizes of 5 or greater. The three clinical factors commonly available for all organ sites in TCGA data, age at diagnosis, sex, and stage, were included in all analyses. Cox proportional hazards models were fit for DSS, estimating hazard ratios (HR) and 95% confidence intervals (CI). The proportional hazards assumption was verified by Schoenfeld residuals. To further establish the nature of the relationship between mutational signatures and DSS, it was also determined whether stage at diagnosis differed according to signature, comparing Stage I to Stage III/IV disease, using the measures and adjustment factors employed in Cox regression, but quantifying relative risks (RR) and 95% CI.

Models were comparted that included only diagnosis age, sex, tumor grade, and disease stage (baseline model) to a model that also included all mutational signatures significantly associated with survival, and also to a third model that incorporated in addition a measure of tumor mutational burden (TMB). A concordance statistic (c-statistic (Harrell et al., 1996), commonly known as c-index) was calculated to compare improvement in model fit with sequential incorporation of these measures. The difference in c-index between the baseline and other models was assessed. Tumor mutational burden was quantified using nonsynonomous somatic mutations and evaluated as both a continuous variable and using cutpoints derived using maximally selected rank statistics (Hothorn 2003). A two-tailed p-value of <0.05, after adjustment for clinical factors and consideration of the false discovery rate, (FDR) (Benjamini et al., 2001) was considered significant.

Results

Of solid tumors, 14 organ sites, constituting 16 distinct pathological entities or cancer types, and 6790 patients were included in the in-depth analysis, as these had at least 50 DSS events (Table 1). (GBM was later excluded due to less than 50 events after consideration of immortal person time). Among cancer types, the number of included patients ranged from 170 for pancreatic adenocarcinoma (PAAD) to over 950 for breast carcinoma (BRCA; n=965). Mean age of included patients ranged from 42.9 years (Low Grade Glioma (LGG)) to 68.1 (Bladder Carcinosarcoma (BLCA)). Signatures of 49 distinct mutational patterns of single base substitution (SBS) were examined in relationship to DSS (Catalogue of Somatic Mutations in Cancer (https://cancer.sanger.ac.uk/cosmic). The proportional hazards assumption was violated for 17 signature-cancer combinations in total (these combinations are SBS2BRCA SBS6BRCA SBS32BRCA, SBS35CESC SBS36CESC, SBS17bCOAD SBS29COAD, SBS15HNSC, SBS14LIHC SBS36LIHC, SBS24LUAD SBS37LUAD, SBS39LUSC, SBS190V SBS10V SBS300V, SBS17aPAAD SBS24PAAD, SBS7aSARC SBS13SARC SBS85SARC) thus HR are presented separately for survival times in which hazards were proportional.

TABLE 1
Selected characteristics of participants in The Cancer
Genome Atlas (TCGA) followed for cancer survival

	Cancer	Events			Stage
Cancer	Cases	(DSS)	Age	Female	1/2/3/4/unknown
Abbreviation	(n)	(n)	(mean)	(%)	(n)

BLCA	393	123	68.0	25.8	2/130/132/129/2
BRCA	917	72	58.0	98.8	162/537/199/19/19
CESC	268	50	47.9	100	0/0/0/0/268
COAD	352	56	66.3	48.1	60/135/101/56/10
HNSC	415	129	60.9	26.1	25/66/73/251/64
LGG	487	111	43.2	25.0	0/0/0/0/487
LIHC	323	75	59.3	32.3	163/78/79/3/21
LUAD	446	108	65.0	54.1	249/106/70/21/7
LUSC	415	87	67.0	25.1	205/135/68/7/4
OV	339	167	59.5	100	0/0/0/0/339
PAAD	163	77	64.6	44.6	16/138/4/5/3
SARC	232	71	60.5	54.7	0/0/0/0/232
SKCM	409	186	58.1	38.3	85/137/165/22/35
STAD	366	98	65.1	34.8	48/122/164/32/11
UCEC	521	57	63.9	100	0/0/0/0/525
*Note:
Case counts reflect only participants who had disease specific survival (DSS) information available, and were restricted to cancers with a minimum of n = 50 DSS events, thus constitute less than the full census of cancer patients enrolled in TCGA. In addition, cases were omitted if a DSS event occurred before or at consent.

Abbreviation Key

• • DSS Disease-specific survival
  • BLCA Bladder Urothelial Carcinoma
  • BRCA Breast invasive carcinoma
  • CESC Cervical squamous cell carcinoma and endocervical adenocarcinoma
  • COAD Colon adenocarcinoma
  • GBM Glioblastoma multiforme
  • HNSC Head and Neck squamous cell carcinoma
  • LGG Brain Lower Grade Glioma
  • LIHC Liver hepatocellular carcinoma
  • LUAD Lung adenocarcinoma
  • LUSC Lung squamous cell carcinoma
  • OV Ovarian serous cystadenocarcinoma
  • PAAD Pancreatic adenocarcinoma
  • SARC Sarcoma
  • SKCM Skin Cutaneous Melanoma
  • STAD Stomach adenocarcinoma
  • UCEC Uterine Corpus Endometrial Carcinoma
    Signatures Associated with DSS

Individuals with specific tumor mutational signatures had altered DSS that exceeded the FDR threshold in all included cancers except Lung squamous carcinoma (LUSC) (L, and Lung Adenocarcinoma (LUAD). Table 2 While results derived using continuous or discrete measures often supported others, only those relationships identified using a single cutpoint and evaluated using hazard ratios are described below.

TABLE 2A
Mutational signatures related to disease-specific survival (DSS), according to each cancer.
Restricted to cancers with DSS events > n = 50, and binary cutpoints with cell sizes > n = 5.

Continuous Signature Results

Discrete Signature Results

Cancer	Sig	Signature Label	HazardRatio	HRLowerCL	HRUpperCL	HazardRatio	HRLowerCL	HRUpperCL

BLCA	SBS1	Endogenous clock-like age	0.981493	0.965658	0.997588	0.978894	0.961871	0.996219
BLCA	SBS2	Endogenous Apobec3a	0.995605	0.992804	0.998415	0.995588	0.992723	0.998462
BLCA	SBS4	Tobacco	0.994808	0.979577	1.010277	0.987826	0.967918	1.008143
BLCA	SBS6	Mismatchrepair	0.992654	0.973406	1.012282	0.987026	0.96299	1.011661
BLCA	SBS7a	UV	0.975196	0.962309	0.988256	0.975966	0.960936	0.991232
BLCA	SBS7b	UV	1.004589	0.979767	1.030041	0.957612	0.916433	1.00064
BLCA	SBS7c	UV	0.95231	0.833246	1.088387	0.928793	0.774834	1.113345
BLCA	SBS7d	UV	0.986684	0.84057	1.158196	0.958651	0.741983	1.238589
BLCA	SBS10a	Polymerase epsilon hyperm	0.996471	0.970314	1.023333	0.820747	0.559875	1.203172
BLCA	SBS10b	Polymerase epsilon mutati	0.990042	0.982087	0.998063	0.990108	0.981636	0.998652
BLCA	SBS12	Liver cancer	0.984294	0.952718	1.016917	0.97669	0.937629	1.017377
BLCA	SBS13	Endogenous apobec	0.995799	0.993197	0.998408	0.995732	0.993059	0.998413
BLCA	SBS14	Mismatchrepair + PolEpsil	0.989273	0.924448	1.058645	0.958284	0.877646	1.046331
BLCA	SBS15	Mismatchrepair	0.993146	0.974565	1.012081	0.99451	0.977124	1.012206
BLCA	SBS16	Unknown	0.967939	0.927363	1.010291	0.940811	0.889059	0.995576
BLCA	SBS17a	Unknown	0.947236	0.855365	1.048975	0.950378	0.831058	1.08683
BLCA	SBS17b	Unknown	0.972663	0.906556	1.043592	0.92679	0.837447	1.025664
BLCA	SBS18	ReactiveOxy	1.058487	1.01784	1.100757	1.081669	1.009753	1.158707
BLCA	SBS19	Unknown	0.986609	0.960585	1.013337	0.994664	0.964713	1.025546
BLCA	SBS20	Mismatchrepair + POLD1mut	0.945328	0.864764	1.033398	0.972045	0.882128	1.071127
BLCA	SBS21	Mismatchrepair	1.033462	0.966284	1.10531	1.079738	0.998225	1.167908
BLCA	SBS22	Aristolochic acid	0.919483	0.858426	0.984883	0.894661	0.819573	0.976629
BLCA	SBS23	Unknown	1.073833	1.011831	1.139634	1.026398	0.943321	1.116792
BLCA	SBS24	Aflatoxin	0.992215	0.968691	1.016311	0.992395	0.963268	1.022403
BLCA	SBS25	Chemotherapy	1.036842	1.007281	1.06727	1.164547	1.011244	1.341091
BLCA	SBS26	Mismatchrepair	0.984583	0.96668	1.002819	0.987106	0.967776	1.006821
BLCA	SBS28	Unknown	0.988981	0.937673	1.043096	0.962429	0.846471	1.094273
BLCA	SBS29	Tobacco chewing in Hollst	0.99986	0.978105	1.022099	0.995	0.967392	1.023396
BLCA	SBS3	Homologous repair	1.000806	0.979675	1.022394	1.002676	0.97274	1.033532
BLCA	SBS30	BER repair-NTHL1mut	0.991043	0.975477	1.006859	0.970452	0.949034	0.992354
BLCA	SBS31	PLChemotherapy	1.019775	0.987932	1.052645	1.000299	0.955673	1.04701
BLCA	SBS32	AZA Chemotherapy	1.019887	0.963777	1.079265	1.015076	0.925738	1.113036
BLCA	SBS33	Unknown	0.98233	0.9326	1.034712	0.979194	0.920987	1.041079
BLCA	SBS34	Unknown	1.347536	1.052641	1.725045	1.982982	1.345558	2.92237
BLCA	SBS35	PLChemotherapy	0.955573	0.838447	1.089061	0.95523	0.801349	1.138659
BLCA	SBS36	BERrepair MUTY	0.916379	0.801653	1.047525	0.932925	0.778009	1.118688
BLCA	SBS38	UV	0.966131	0.90372	1.032852	0.974104	0.909813	1.042938
BLCA	SBS39	Unknown	0.990313	0.981808	0.998891	0.988311	0.979036	0.997674
BLCA	SBS42	Haloalkane	1.009078	0.971414	1.048202	1.011931	0.958971	1.067815
BLCA	SBS11	Temozolo Chemotherapy	1.115308	0.939952	1.323379	0.916931	0.58353	1.440821
BLCA	SBS37	Unknown	0.973116	0.910454	1.04009	0.964407	0.883433	1.052803
BLCA	SBS40	Unknown	0.154996	3.6E−92	6.67E+89
BLCA	SBS41	Unknown	0.857324	0.593469	1.238489	0.00926	0
BLCA	SBS44	Mismatchrepair	1.091343	1.004711	1.185445	116.4983	0
BLCA	SBS8	Unknown	1.008418	0.963024	1.055952	0.971945	0.897014	1.053136
BLCA	SBS84	Actind cytidinedeaminase	1.046867	0.987062	1.110296	1.019631	0.930298	1.117542
BLCA	SBS85	Actind cytidinedeaminase	0.997559	0.818709	1.21548	1.279738	0.882849	1.855051
BLCA	SBS9	PolETA Somatichypermutation	5.716394	1.747194	18.70266
BRCA	SBS1	Endogenous clock-like age	1.005151	0.99511	1.015293	1.004493	0.993762	1.015339
BRCA	SBS2	Endogenous Apobec3a	1.002796	1.001566	1.004027	1.002653	1.001403	1.003905
BRCA	SBS4	Tobacco	0.99597	0.944625	1.050105	0.948519	0.872508	1.031152
BRCA	SBS6	Mismatchrepair	0.999889	0.981811	1.018299	0.997224	0.973373	1.02166
BRCA	SBS7a	UV	1.011896	1.003625	1.020235	1.013435	1.005037	1.021904
BRCA	SBS7b	UV	0.997215	0.922383	1.078118	1.013224	0.965066	1.063785
BRCA	SBS7c	UV	0.96059	0.738479	1.249506	0.967447	0.666592	1.404087
BRCA	SBS7d	UV	1.050139	0.877605	1.256592	1.028746	0.784455	1.349114
BRCA	SBS8	Unknown	0.991645	0.939701	1.04646	0.989926	0.92369	1.060911
BRCA	SBS10a	Polymerase epsilon hyperm	0.863984	0.685736	1.088566	0.716018	0.481665	1.064396
BRCA	SBS10b	Polymerase epsilon mutati	1.009437	1.000058	1.018904	1.008503	0.998514	1.018591
BRCA	SBS11	Temozolo Chemotherapy	0.995307	0.850184	1.165203	1.017333	0.86021	1.203156
BRCA	SBS12	Liver cancer	1.043356	0.916251	1.188092	1.079798	0.897052	1.299773
BRCA	SBS13	Endogenous apobec	1.002114	1.001172	1.003056	1.001979	1.001029	1.002931
BRCA	SBS14	Mismatchrepair + PolEpsil	0.820902	0.598964	1.125076	0.889107	0.615412	1.284524
BRCA	SBS15	Mismatchrepair	1.007454	0.992186	1.022958	1.008658	0.99341	1.024141
BRCA	SBS16	Unknown	0.956844	0.826918	1.107185	0.973377	0.788042	1.2023
BRCA	SBS17a	Unknown	0.93195	0.769594	1.128557	0.844644	0.632671	1.127637
BRCA	SBS17b	Unknown	0.908818	0.701891	1.176752	1.032503	0.802341	1.32869
BRCA	SBS18	ReactiveOxy	0.968731	0.859344	1.092042	0.834336	0.675226	1.030938
BRCA	SBS19	Unknown	0.999075	0.951536	1.048988	0.997492	0.947565	1.05005
BRCA	SBS21	Mismatchrepair	0.841636	0.661964	1.070074	0.852166	0.634966	1.143661
BRCA	SBS22	Aristolochic acid	1.03463	0.95187	1.124586	1.029411	0.936566	1.131459
BRCA	SBS23	Unknown	0.864286	0.633178	1.179748	0.784969	0.474318	1.299079
BRCA	SBS24	Aflatoxin	0.992185	0.95253	1.033491	0.955238	0.871652	1.046841
BRCA	SBS25	Chemotherapy	1.050591	0.999666	1.104109	1.116039	1.029008	1.21043
BRCA	SBS26	Mismatchrepair	0.988276	0.927324	1.053233	0.993173	0.952044	1.036079
BRCA	SBS28	Unknown	0.907025	0.612072	1.344113	0.977119	0.556527	1.715571
BRCA	SBS29	Tobacco chewing in Hollst	1.02975	0.993758	1.067045	1.046227	1.009165	1.084649
BRCA	SBS20	Mismatchrepair + POLD1mut	1.002452	0.98298	1.022311	0.997727	0.972327	1.02379
BRCA	SBS30	BER repair-NTHL1mut	1.0388	1.005039	1.073694	1.038067	0.991869	1.086415
BRCA	SBS31	PLChemotherapy	0.990496	0.891841	1.100065	1.005322	0.860674	1.17428
BRCA	SBS32	AZA Chemotherapy	1.003092	0.975355	1.031617	0.999972	0.938482	1.065491
BRCA	SBS33	Unknown	1.010039	0.916964	1.112562	1.009733	0.905516	1.125944
BRCA	SBS34	Unknown	0.698516	0.452543	1.078183	0.643019	0.320215	1.291235
BRCA	SBS35	PLChemotherapy	0.970123	0.854779	1.101032	0.995447	0.851478	1.163758
BRCA	SBS36	BERrepair MUTY	1.039906	0.976171	1.107801	1.030396	0.948717	1.119106
BRCA	SBS37	Unknown	1.025153	0.956303	1.098959	1.001732	0.904579	1.109321
BRCA	SBS38	UV	0.945386	0.758649	1.178087	0.877788	0.624497	1.233812
BRCA	SBS39	Unknown	1.010101	0.999943	1.020361	1.00834	0.997187	1.019619
BRCA	SBS42	Haloalkane	1.015958	0.95234	1.083825	1.04825	0.976674	1.125072
BRCA	SBS84	Actind cytidinedeaminase	0.829367	0.618271	1.112536	0.89813	0.618701	1.303761
BRCA	SBS85	Actind cytidinedeaminase	1.020952	0.84485	1.233762	0.92979	0.689695	1.253466
BRCA	SBS3	Homologous repair	0.995769	0.951626	1.041959	0.960177	0.892286	1.033233
BRCA	SBS40	Unknown	0.93458	0.73552	1.187514	0.277338	0
BRCA	SBS41	Unknown	0.118976	0.000695	20.38172	0.017993	0
BRCA	SBS44	Mismatchrepair	1.025657	0.966732	1.088175	1.039621	0.948128	1.139943
BRCA	SBS9	PolETA Somatichypermutati	1.321147	0.946648	1.843802	1.812665	0.307464	10.68665
CESC	SBS1	Endogenous clock-like age	0.978954	0.955263	1.003233	0.980983	0.95685	1.005726
CESC	SBS2	Endogenous Apobec3a	0.998277	0.995037	1.001526	0.998384	0.995157	1.001622
CESC	SBS4	Tobacco	0.981276	0.923865	1.042256	0.960829	0.787895	1.171721
CESC	SBS6	Mismatchrepair	0.999093	0.99278	1.005447	0.999029	0.991982	1.006127
CESC	SBS7a	UV	0.993287	0.980672	1.006065	0.994859	0.981703	1.008191
CESC	SBS7b	UV	0.980414	0.915376	1.050074	0.998493	0.982488	1.014759
CESC	SBS7c	UV	1.064032	0.892175	1.268993	1.02342	0.787229	1.330475
CESC	SBS7d	UV	1.005493	0.841433	1.20154	1.24957	0.931639	1.675999
CESC	SBS8	Unknown	1.053155	1.003737	1.105005	1.025478	0.951272	1.105473
CESC	SBS10a	Polymerase epsilon hyperm	0.993174	0.942461	1.046616	0.990191	0.912818	1.074122
CESC	SBS10b	Polymerase epsilon mutati	0.992011	0.97956	1.00462	0.993024	0.980234	1.005981
CESC	SBS11	Temozolo Chemotherapy	0.842997	0.562201	1.264038	0.002785	0
CESC	SBS12	Liver cancer	1.03684	0.899382	1.195306	1.045708	0.832922	1.312855
CESC	SBS13	Endogenous apobec	0.999251	0.997057	1.00145	0.999369	0.997231	1.001511
CESC	SBS14	Mismatchrepair + PolEpsil	0.96964	0.877581	1.071357	0.959805	0.839842	1.096904
CESC	SBS15	Mismatchrepair	0.991113	0.970124	1.012557	0.979463	0.93577	1.025196
CESC	SBS16	Unknown	0.918261	0.740065	1.139363	0.860741	0.639592	1.158355
CESC	SBS17a	Unknown	1.068158	0.981877	1.162022	1.077578	0.985229	1.178582
CESC	SBS17b	Unknown	1.001765	0.959987	1.045361	0.995787	0.94333	1.05116
CESC	SBS18	ReactiveOxy	1.031284	0.966715	1.100164	1.052225	0.937816	1.180592
CESC	SBS19	Unknown	1.059596	0.964393	1.164196	1.148172	0.995342	1.324468
CESC	SBS21	Mismatchrepair	0.973777	0.879401	1.078283	0.95227	0.79585	1.139433
CESC	SBS22	Aristolochic acid	0.977242	0.857979	1.113084	0.986642	0.853398	1.140689
CESC	SBS23	Unknown	1.077091	0.935198	1.240512	59.57349	0
CESC	SBS24	Aflatoxin	1.0268	0.985766	1.069541	1.042163	0.990456	1.096569
CESC	SBS25	Chemotherapy	1.000613	0.969628	1.032588	0.366643	0
CESC	SBS26	Mismatchrepair	0.992997	0.9593	1.027877	0.976246	0.93362	1.020818
CESC	SBS28	Unknown	0.904318	0.409056	1.999216	0.290392	0.01155	7.300808
CESC	SBS29	Tobacco chewing in Hollst	0.992533	0.926289	1.063515	1.002401	0.916336	1.09655
CESC	SBS20	Mismatchrepair + POLD1mut	1.008969	0.968999	1.050589	1.000722	0.948006	1.056369
CESC	SBS30	BER repair-NTHL1mut	1.040215	0.952702	1.135768	1.034728	0.90886	1.178028
CESC	SBS31	PLChemotherapy	1.005635	0.94218	1.073364	1.050309	0.96385	1.144523
CESC	SBS32	AZA Chemotherapy	1.00299	0.822731	1.222744	2.504853	0.814407	7.704118
CESC	SBS33	Unknown	1.000529	0.981659	1.019761	1.004855	0.986759	1.023283
CESC	SBS34	Unknown	1.475118	0.949296	2.292198	0.75838	0.367714	1.564096
CESC	SBS35	PLChemotherapy	1.05777	0.944929	1.184087	0.984368	0.852715	1.136348
CESC	SBS36	BERrepair MUTY	0.964674	0.854099	1.089565	0.905482	0.730005	1.123139
CESC	SBS37	Unknown	0.99418	0.963591	1.02574	0.978348	0.912799	1.048603
CESC	SBS38	UV	1.073163	0.929041	1.239643	1.012367	0.81805	1.252841
CESC	SBS39	Unknown	1.001248	0.988016	1.014657	1.005744	0.992769	1.01889
CESC	SBS39	Unknown	1.001248	0.988016	1.014657	1.005744	0.992769	1.01889
CESC	SBS42	Haloalkane	1.204991	1.072986	1.353236	1.195688	0.955721	1.495907
CESC	SBS84	Actind cytidinedeaminase	0.958246	0.802558	1.144137	0.943429	0.761538	1.168763
CESC	SBS85	Actind cytidinedeaminase	1.187077	0.748517	1.882592	16.9875	0.76848	375.5141
CESC	SBS3	Homologous repair	1.020689	0.977519	1.065767	0.122168	0
CESC	SBS40	Unknown
CESC	SBS41	Unknown	0.969426	0.829908	1.132399	1656.58	0
CESC	SBS44	Mismatchrepair	1.267903	0.956554	1.680593	894.468	0
CESC	SBS9	PolETA Somatichypermutati	1.072014	0.839379	1.369125	0.774022	0.430598	1.391346
COAD	SBS1	Endogenous clock-like age	1.00023	0.998589	1.001875	1.000277	0.99864	1.001917
COAD	SBS2	Endogenous Apobec3a	0.995976	0.964133	1.028871	1.002065	0.977475	1.027273
COAD	SBS4	Tobacco	0.992313	0.966367	1.018957	1.015139	0.984543	1.046685
COAD	SBS6	Mismatchrepair	1.00053	0.999098	1.001964	1.0005	0.998988	1.002014
COAD	SBS7a	UV	0.978869	0.917947	1.043833	0.989746	0.916951	1.06832
COAD	SBS7b	UV	0.992435	0.968395	1.017072	0.987307	0.955036	1.020669
COAD	SBS7c	UV	0.861032	0.722652	1.02591	0.733211	0.558835	0.961998
COAD	SBS7d	UV	0.972274	0.88869	1.063719	0.921281	0.759021	1.118228
COAD	SBS8	Unknown	1.007757	0.962574	1.055062	1.053446	0.982435	1.129589
COAD	SBS10a	Polymerase epsilon hyperm	1.000455	0.999571	1.00134	1.000322	0.999373	1.001271
COAD	SBS10b	Polymerase epsilon mutati	1.000443	0.999977	1.00091	1.000394	0.999921	1.000867
COAD	SBS11	Temozolo Chemotherapy	1.012707	0.997254	1.0284	6.451911	0.11413	364.7335
COAD	SBS12	Liver cancer	0.992814	0.916086	1.075969	1.045024	0.860883	1.268552
COAD	SBS13	Endogenous apobec	0.990008	0.914754	1.071453	0.990713	0.905006	1.084537
COAD	SBS14	Mismatchrepair + PolEpsil	1.000637	0.993928	1.007392	0.997327	0.985288	1.009513
COAD	SBS15	Mismatchrepair	1.000411	0.999364	1.00146	1.00025	0.99916	1.00134
COAD	SBS16	Unknown	0.992494	0.851271	1.157147	1.057905	0.84366	1.326557
COAD	SBS17a	Unknown	1.029089	1.001946	1.056967	1.031911	1.003708	1.060907
COAD	SBS17b	Unknown	1.006838	0.99814	1.015613	1.006412	0.997641	1.015259
COAD	SBS18	ReactiveOxy	1.00927	0.987764	1.031244	1.013097	0.987492	1.039367
COAD	SBS19	Unknown	1.003313	0.929518	1.082967	0.99311	0.902581	1.092719
COAD	SBS21	Mismatchrepair	1.004546	0.999862	1.009251	1.003525	0.997984	1.009096
COAD	SBS22	Aristolochic acid	1.00105	0.987504	1.014781	0.998644	0.982396	1.01516
COAD	SBS23	Unknown	1.003721	0.957272	1.052424	0.988424	0.900846	1.084515
COAD	SBS24	Aflatoxin	1.006731	0.983608	1.030397	1.005823	0.978106	1.034325
COAD	SBS25	Chemotherapy	1.079391	1.022887	1.139016	1.007072	0.913725	1.109955
COAD	SBS26	Mismatchrepair	1.001962	0.999211	1.00472	0.99979	0.996276	1.003317
COAD	SBS28	Unknown	1.001527	0.998337	1.004728	1.00124	0.997878	1.004613
COAD	SBS29	Tobacco chewing in Hollst	0.976737	0.945671	1.008824	0.997083	0.960826	1.034707
COAD	SBS20	Mismatchrepair + POLD1mut	1.001773	0.996312	1.007265	1.001022	0.992559	1.009557
COAD	SBS30	BER repair-NTHL1mut	1.005782	0.975678	1.036815	0.982929	0.921481	1.048474
COAD	SBS31	PLChemotherapy	0.974186	0.910914	1.041852	0.994282	0.910341	1.085963
COAD	SBS32	AZA Chemotherapy	0.955121	0.839423	1.086765	0.979473	0.806939	1.188896
COAD	SBS33	Unknown	1.020055	1.004201	1.03616	1.017277	0.999369	1.035506
COAD	SBS34	Unknown	1.021734	0.957263	1.090547	1.030511	0.955226	1.11173
COAD	SBS35	PLChemotherapy	0.993356	0.942994	1.046407	1.000926	0.934312	1.072289
COAD	SBS36	BERrepair MUTY	1.022147	1.006287	1.038258	1.043678	0.991829	1.098238
COAD	SBS37	Unknown	1.00002	0.990424	1.009709	0.998048	0.985468	1.010789
COAD	SBS38	UV	1.028867	0.978915	1.081367	1.021228	0.958884	1.087627
COAD	SBS39	Unknown	1.003501	0.99166	1.015483	1.004772	0.993598	1.016071
COAD	SBS42	Haloalkane	1.007971	1.000321	1.01568	1.017601	1.000163	1.035343
COAD	SBS84	Actind cytidinedeaminase	0.999	0.970908	1.027905	0.969387	0.913587	1.028595
COAD	SBS85	Actind cytidinedeaminase	0.99257	0.930052	1.05929	1.72825	0.70778	4.220019
COAD	SBS3	Homologous repair	1.032988	0.995147	1.072268	1.751105	0
COAD	SBS40	Unknown	2.49E−11	0
COAD	SBS41	Unknown	0.994381	0.767235	1.288774	4.76E+28	0
COAD	SBS44	Mismatchrepair	1.059697	0.927449	1.210802	0.457852	0
COAD	SBS9	PolETA Somatichypermutation	1.035875	1.016589	1.055526	1.05762	0.991097	1.128609
HNSC	SBS1	Endogenous clock-like age	0.991593	0.974633	1.008849	0.993271	0.975969	1.010881
HNSC	SBS2	Endogenous Apobec3a	0.99895	0.993735	1.004191	0.998579	0.993064	1.004124
HNSC	SBS4	Tobacco	0.997272	0.993369	1.00119	0.996046	0.991625	1.000488
HNSC	SBS6	Mismatchrepair	0.99326	0.978594	1.008145	0.993745	0.975384	1.012453
HNSC	SBS7a	UV	1.000415	0.989516	1.011434	0.996678	0.982526	1.011034
HNSC	SBS7a	UV	1.000415	0.989516	1.011434	0.996678	0.982526	1.011034
HNSC	SBS7b	UV	0.982973	0.954936	1.011833
HNSC	SBS7c	UV	1.048905	0.946442	1.162461	1.079715	0.930373	1.253029
HNSC	SBS7d	UV	0.98962	0.901157	1.086767	1.004581	0.9025	1.118209
HNSC	SBS8	Unknown	1.025664	0.993834	1.058514	1.024545	0.971481	1.080508
HNSC	SBS10a	Polymerase epsilon hyperm	1.067807	0.923518	1.234641	1.124371	0.906569	1.394499
HNSC	SBS10b	Polymerase epsilon mutati	0.993443	0.977987	1.009143	0.996495	0.980857	1.012383
HNSC	SBS11	Temozolo Chemotherapy	0.859966	0.708049	1.044477	0.880707	0.63532	1.220873
HNSC	SBS12	Liver cancer	0.974568	0.912113	1.0413	0.960975	0.878931	1.050677
HNSC	SBS13	Endogenous apobec	0.998464	0.994191	1.002755	0.998018	0.99357	1.002487
HNSC	SBS14	Mismatchrepair + PolEpsil	0.971889	0.865439	1.091432	0.906288	0.728207	1.127918
HNSC	SBS15	Mismatchrepair	0.983139	0.956136	1.010904	0.990173	0.960399	1.02087
HNSC	SBS16	Unknown	1.017345	0.993229	1.042046	1.014953	0.9848	1.046029
HNSC	SBS17a	Unknown	1.008119	0.937284	1.084308	0.997858	0.909645	1.094627
HNSC	SBS17b	Unknown	0.996064	0.858611	1.155521	0.970951	0.78535	1.200414
HNSC	SBS18	ReactiveOxy	0.980634	0.942708	1.020085	0.971843	0.919007	1.027716
HNSC	SBS19	Unknown	0.982463	0.949241	1.016848	0.986323	0.946011	1.028353
HNSC	SBS21	Mismatchrepair	0.997224	0.974708	1.020261	0.966282	0.876334	1.065462
HNSC	SBS22	Aristolochic acid	0.96274	0.915546	1.012367	0.977532	0.9216	1.036858
HNSC	SBS23	Unknown	0.984571	0.929603	1.04279	0.910601	0.817975	1.013716
HNSC	SBS24	Aflatoxin	0.997819	0.985898	1.009884	0.991347	0.976619	1.006297
HNSC	SBS25	Chemotherapy	1.00135	0.977338	1.025951	0.986122	0.945699	1.028273
HNSC	SBS26	Mismatchrepair	0.965096	0.927984	1.003693	0.928177	0.874629	0.985003
HNSC	SBS28	Unknown	1.092198	0.735927	1.620943	1.328343	0.728783	2.421153
HNSC	SBS29	Tobacco chewing in Hollst	1.031952	1.003785	1.060909	1.02063	0.985194	1.057341
HNSC	SBS20	Mismatchrepair + POLD1mut	0.949256	0.869078	1.036832	0.93422	0.8196	1.064869
HNSC	SBS30	BER repair-NTHL1mut	0.989794	0.969022	1.011012	0.9819	0.956164	1.008328
HNSC	SBS31	PLChemotherapy	1.023428	0.998071	1.049429	1.011066	0.976981	1.04634
HNSC	SBS32	AZA Chemotherapy	1.037123	0.984435	1.09263	1.047686	0.971545	1.129795
HNSC	SBS33	Unknown	0.994522	0.941048	1.051035	0.993138	0.934449	1.055513
HNSC	SBS34	Unknown	1.138389	0.958674	1.351795	1.237414	0.932415	1.642179
HNSC	SBS35	PLChemotherapy	1.006011	0.981712	1.030911	1.002378	0.956703	1.050233
HNSC	SBS36	BERrepair MUTY	1.039448	0.98893	1.092546	1.015131	0.938474	1.098048
HNSC	SBS38	UV	1.008821	0.963929	1.055803	1.024244	0.973755	1.07735
HNSC	SBS39	Unknown	1.000981	0.995482	1.006509	1.001314	0.995702	1.006958
HNSC	SBS42	Haloalkane	1.005441	0.948642	1.065641	0.991758	0.912178	1.07828
HNSC	SBS84	Actind cytidinedeaminase	1.080561	0.991173	1.17801	1.0654	0.900856	1.259998
HNSC	SBS3	Homologous repair	1.071467	1.007193	1.139843	0.980429	0.862822	1.114067
HNSC	SBS37	Unknown	1.004859	0.901498	1.120072	0.856978	0.701356	1.04713
HNSC	SBS40	Unknown	1.276271	1.0443	1.559771	0.165969	0
HNSC	SBS41	Unknown	1.010676	0.85206	1.198818	3.15E−09	0
HNSC	SBS44	Mismatchrepair	1.091642	0.831629	1.432948	1.79505	0.728752	4.421543
HNSC	SBS85	Actind cytidinedeaminase	1.107256	1.006628	1.217943	1.440022	1.181002	1.755852
HNSC	SBS9	PolETA Somatichypermutati	1.694576	1.261187	2.276893	6940.55	0
LGG	SBS1	Endogenous clock-like age	1.003849	0.998432	1.009296	1.0037	0.998162	1.009269
LGG	SBS2	Endogenous Apobec3a	0.915614	0.703898	1.191009	0.938527	0.63325	1.390971
LGG	SBS4	Tobacco	0.995277	0.895766	1.105844	0.854104	0.679058	1.074273
LGG	SBS6	Mismatchrepair	1.010371	0.965148	1.057713	1.006497	0.936812	1.081365
LGG	SBS7a	UV	1.020366	0.887536	1.173074	1.0945	0.900758	1.329913
LGG	SBS7b	UV	0.980006	0.889345	1.079909	1.063554	0.930402	1.215763
LGG	SBS7c	UV	0.795322	0.565473	1.118596	0.845477	0.457405	1.562798
LGG	SBS7d	UV	0.955279	0.80808	1.129293	1.158278	0.94104	1.425665
LGG	SBS8	Unknown	1.146936	1.016015	1.294728	0.942425	0.775298	1.145579
LGG	SBS10a	Polymerase epsilon hyperm	1.025229	0.751977	1.397774	1.188348	0.714198	1.977282
LGG	SBS10b	Polymerase epsilon mutati	1.09562	1.004562	1.194933	1.104198	0.992366	1.228632
LGG	SBS11	Temozolo Chemotherapy	1.08679	0.892234	1.323771	1.064778	0.792431	1.430727
LGG	SBS12	Liver cancer	0.838783	0.743406	0.946397	0.731309	0.596599	0.896435
LGG	SBS13	Endogenous apobec	1.066058	0.992696	1.144841	1.061794	0.977836	1.152961
LGG	SBS14	Mismatchrepair + PolEpsil	1.330013	0.905882	1.952721	2.127037	0.896995	5.043823
LGG	SBS15	Mismatchrepair	0.983168	0.94874	1.018845	0.996205	0.95165	1.042846
LGG	SBS16	Unknown	0.938527	0.852605	1.033108	0.934937	0.821165	1.064472
LGG	SBS17a	Unknown	1.008278	0.841953	1.20746	0.986221	0.765878	1.269958
LGG	SBS17b	Unknown	0.982815	0.699456	1.380968	1.14253	0.504078	2.58963
LGG	SBS18	ReactiveOxy	1.083014	0.596079	1.967724	1.500636	0.376674	5.978409
LGG	SBS19	Unknown	0.965009	0.877934	1.060719	1.048148	0.896585	1.225333
LGG	SBS21	Mismatchrepair	0.878558	0.74484	1.036281	0.979436	0.773813	1.239698
LGG	SBS22	Aristolochic acid	0.98358	0.832629	1.161897	0.986017	0.790459	1.229957
LGG	SBS23	Unknown	0.939589	0.829053	1.064864	1.112411	0.906434	1.365195
LGG	SBS24	Aflatoxin	1.009456	0.922938	1.104085	1.042299	0.916618	1.185214
LGG	SBS25	Chemotherapy	2.128056	1.443883	3.13642	4.105155	0.867341	19.42985
LGG	SBS26	Mismatchrepair	0.960482	0.853846	1.080434	0.946073	0.795843	1.124662
LGG	SBS28	Unknown	1.129441	0.806455	1.581782	1.486521	0.746325	2.960837
LGG	SBS29	Tobacco chewing in Hollst	1.116807	0.931281	1.339292	1.144964	0.836561	1.56706
LGG	SBS20	Mismatchrepair + POLD1mut	1.150864	0.855777	1.547703	1.247044	0.757096	2.054058
LGG	SBS30	BER repair-NTHL1mut	1.10099	1.000954	1.211023	1.098096	0.949295	1.270223
LGG	SBS31	PLChemotherapy	1.049579	0.99773	1.104121	1.069781	0.999307	1.145224
LGG	SBS32	AZA Chemotherapy	1.07512	0.944991	1.223168	1.132795	0.931515	1.377568
LGG	SBS33	Unknown	1.089641	0.941863	1.260606	1.191672	1.001509	1.417942
LGG	SBS34	Unknown	0.817269	0.524693	1.272989	0.496233	0.199116	1.236702
LGG	SBS35	PLChemotherapy	1.080439	0.871383	1.339651	0.996577	0.725136	1.369625
LGG	SBS36	BERrepair MUTY	1.035687	0.835756	1.283446	1.208931	0.815667	1.791803
LGG	SBS37	Unknown	0.987466	0.873641	1.116121	0.967988	0.801319	1.169322
LGG	SBS38	UV	0.949489	0.718749	1.254303	0.947355	0.590446	1.520008
LGG	SBS39	Unknown	1.004678	0.976534	1.033633	1.000072	0.965756	1.035607
LGG	SBS42	Haloalkane	0.973503	0.89247	1.061892	1.048601	0.88627	1.240666
LGG	SBS84	Actind cytidinedeaminase	0.976813	0.84591	1.127972	1.059257	0.857185	1.308965
LGG	SBS85	Actind cytidinedeaminase	0.816204	0.549722	1.211864	0.38743	0.139737	1.074177
LGG	SBS3	Homologous repair	1.177467	0.995106	1.393247	1.042015	0.631358	1.71978
LGG	SBS40	Unknown	0.001136	0
LGG	SBS41	Unknown	0.468142	0.081875	2.676735	4.22E+20	0
LGG	SBS44	Mismatchrepair	1.106821	0.829875	1.47619	1.342105	0.811105	2.220731
LGG	SBS9	PolETA Somatichypermutati	1.267519	0.989671	1.623372	343147.9	0
LIHC	SBS1	Endogenous clock-like age	1.016283	1.008607	1.024017	1.015435	1.007567	1.023366
LIHC	SBS2	Endogenous Apobec3a	1.011933	0.914903	1.119254	1.026614	0.906947	1.16207
LIHC	SBS3	Homologous repair	0.977431	0.938783	1.01767	0.929853	0.855759	1.010363
LIHC	SBS4	Tobacco	1.002796	0.993868	1.011804	1.001872	0.990756	1.013112
LIHC	SBS6	Mismatchrepair	0.961855	0.924659	1.000547	0.995889	0.943286	1.051424
LIHC	SBS7a	UV	1.044215	0.99658	1.094127	1.037323	0.981377	1.096457
LIHC	SBS7b	UV	0.994797	0.948588	1.043257	0.993853	0.932099	1.059698
LIHC	SBS7d	UV	0.994814	0.902631	1.096413	1.020624	0.897236	1.160981
LIHC	SBS8	Unknown	1.008543	0.98158	1.036247	1.008488	0.975854	1.042213
LIHC	SBS10a	Polymerase epsilon hyperm	0.959996	0.783997	1.175506	1.20572	0.875365	1.66075
LIHC	SBS10b	Polymerase epsilon mutati	1.041346	0.917256	1.182222	1.063558	0.87182	1.297463
LIHC	SBS11	Temozolo Chemotherapy	0.995816	0.843009	1.176322	0.884131	0.642348	1.216924
LIHC	SBS12	Liver cancer	1.004586	0.975238	1.034816	1.010468	0.973897	1.048412
LIHC	SBS13	Endogenous apobec	1.031801	0.908913	1.171303	1.095449	0.936185	1.281807
LIHC	SBS14	Mismatchrepair + PolEpsil	1.222454	1.000806	1.49319	1.606033	1.101588	2.341476
LIHC	SBS15	Mismatchrepair	1.00744	1.003591	1.011305	1.006297	1.002306	1.010304
LIHC	SBS16	Unknown	0.978565	0.942288	1.016239	0.984608	0.944422	1.026504
LIHC	SBS17a	Unknown	1.005486	0.952283	1.061661	1.010323	0.956122	1.067596
LIHC	SBS17b	Unknown	1.108402	0.97977	1.253924	1.141418	0.974291	1.337212
LIHC	SBS18	ReactiveOxy	1.028773	0.96538	1.096328	1.047272	0.951071	1.153204
LIHC	SBS19	Unknown	1.015768	0.993375	1.038666	1.019594	0.996388	1.043341
LIHC	SBS21	Mismatchrepair	1.023993	1.011558	1.03658	1.025527	1.009658	1.041646
LIHC	SBS22	Aristolochic acid	0.999747	0.994342	1.005181	0.999197	0.992677	1.005759
LIHC	SBS23	Unknown	1.039039	0.949307	1.137253	1.060356	0.909066	1.236823
LIHC	SBS24	Aflatoxin	1.016459	1.008335	1.024648	1.016213	1.007366	1.025137
LIHC	SBS25	Chemotherapy	0.998161	0.988939	1.00747	0.99754	0.988956	1.006198
LIHC	SBS26	Mismatchrepair	1.00457	0.996143	1.013069	1.005281	0.995934	1.014715
LIHC	SBS28	Unknown	0.980223	0.802408	1.197441	1.021428	0.821169	1.270525
LIHC	SBS29	Tobacco chewing in Hollst	0.96731	0.900496	1.039081	0.968794	0.881732	1.064452
LIHC	SBS20	Mismatchrepair + POLD1mut	1.080048	0.887146	1.314895	0.847351	0.602369	1.191966
LIHC	SBS30	BER repair-NTHL1mut	0.984772	0.926955	1.046194	0.977465	0.88697	1.077193
LIHC	SBS31	PLChemotherapy	0.994002	0.942432	1.048393	0.962134	0.874155	1.058969
LIHC	SBS32	AZA Chemotherapy	0.909992	0.789362	1.049057	1.079981	0.871324	1.338605
LIHC	SBS33	Unknown	0.976716	0.908711	1.04981	0.983237	0.923436	1.04691
LIHC	SBS34	Unknown	0.990085	0.817129	1.19965	0.820617	0.628429	1.07158
LIHC	SBS35	PLChemotherapy	1.002977	0.970841	1.036178	0.994215	0.953368	1.036812
LIHC	SBS36	BERrepair MUTY	0.970027	0.890529	1.056623	1.007188	0.882742	1.149178
LIHC	SBS37	Unknown	0.959163	0.853197	1.07829	0.901124	0.701812	1.15704
LIHC	SBS38	UV	1.061189	0.965564	1.166284	1.064031	0.928562	1.219264
LIHC	SBS39	Unknown	1.019986	0.998034	1.04242	1.028696	1.003093	1.054953
LIHC	SBS42	Haloalkane	1.009355	0.974057	1.045933	1.026193	0.972051	1.083351
LIHC	SBS85	Actind cytidinedeaminase	1.084205	1.034136	1.136697	6.574555	0
LIHC	SBS40	Unknown	0.921766	0.745197	1.140172	0.025331	0
LIHC	SBS41	Unknown	0.527926	0.019908	13.99937	0.002892	0
LIHC	SBS44	Mismatchrepair	1.052659	0.923152	1.200335	0.609617	0.328528	1.131207
LIHC	SBS7c	UV	0.729627	0.5366	0.992089	0.332377	0.174715	0.63231
LIHC	SBS84	Actind cytidinedeaminase	1.021352	0.969342	1.076153	1.021525	0.919905	1.134372
LIHC	SBS9	PolETA Somatichypermutati	0.602594	0.210971	1.72118	0.000265	0
LUAD	SBS1	Endogenous clock-like age	0.991606	0.971697	1.011923	0.997153	0.97674	1.017992
LUAD	SBS2	Endogenous Apobec3a	1.000465	0.993613	1.007364	1.000353	0.992981	1.00778
LUAD	SBS3	Homologous repair	1.016873	0.979727	1.055427	1.075249	0.96686	1.195788
LUAD	SBS4	Tobacco	0.999642	0.998594	1.000691	0.999325	0.998144	1.000509
LUAD	SBS6	Mismatchrepair	1.004702	0.99913	1.010304	1.003803	0.997766	1.009877
LUAD	SBS7a	UV	1.012503	0.996506	1.028756	1.012011	0.993946	1.030404
LUAD	SBS7b	UV	0.999109	0.979756	1.018845	0.998243	0.974708	1.022347
LUAD	SBS7c	UV	0.699439	0.495535	0.987246	0.854917	0.533956	1.368808
LUAD	SBS7d	UV	0.940897	0.840633	1.05312	0.946453	0.784986	1.141131
LUAD	SBS8	Unknown	0.997129	0.887829	1.119884	1.047879	0.833096	1.318036
LUAD	SBS10a	Polymerase epsilon hyperm	0.896747	0.800497	1.00457	0.89426	0.764899	1.045499
LUAD	SBS10b	Polymerase epsilon mutati	1.018248	0.993011	1.044126	1.011561	0.98147	1.042574
LUAD	SBS11	Temozolo Chemotherapy	1.02779	0.899817	1.173963	0.988366	0.757475	1.289637
LUAD	SBS12	Liver cancer	1.051742	1.004895	1.100774	1.040364	0.976105	1.108854
LUAD	SBS13	Endogenous apobec	1.000645	0.994791	1.006535	1.000316	0.994252	1.006417
LUAD	SBS14	Mismatchrepair + PolEpsil	0.989883	0.940231	1.042156	0.956518	0.887111	1.031356
LUAD	SBS15	Mismatchrepair	0.999564	0.984402	1.014959	0.998197	0.98172	1.014951
LUAD	SBS16	Unknown	0.978753	0.916835	1.044853	0.985497	0.887003	1.094929
LUAD	SBS17a	Unknown	0.948878	0.878925	1.024399	0.952065	0.870169	1.041669
LUAD	SBS17b	Unknown	1.068191	1.000555	1.140399	1.043955	0.954231	1.142116
LUAD	SBS18	ReactiveOxy	0.991654	0.948153	1.037149	0.969642	0.904192	1.03983
LUAD	SBS19	Unknown	1.004418	0.987106	1.022034	1.009423	0.991512	1.027657
LUAD	SBS21	Mismatchrepair	1.008957	0.990447	1.027813	1.016535	0.99925	1.03412
LUAD	SBS22	Aristolochic acid	0.989742	0.960805	1.019551	0.995219	0.959505	1.032261
LUAD	SBS23	Unknown	1.012143	0.932725	1.098323	1.034052	0.917819	1.165004
LUAD	SBS24	Aflatoxin	0.995095	0.98871	1.001521	0.994623	0.987479	1.00182
LUAD	SBS25	Chemotherapy	1.019513	0.999485	1.039942	1.008303	0.979865	1.037566
LUAD	SBS26	Mismatchrepair	0.997977	0.982877	1.01331	0.998994	0.983327	1.014909
LUAD	SBS28	Unknown	1.265665	0.998198	1.6048	1.251199	0.845219	1.852182
LUAD	SBS29	Tobacco chewing in Hollst	1.004529	0.992557	1.016645	0.99847	0.981081	1.016167
LUAD	SBS20	Mismatchrepair + POLD1mut	0.986058	0.947811	1.025849	1.010597	0.955846	1.068485
LUAD	SBS30	BER repair-NTHL1mut	0.999545	0.9811	1.018336	1.013959	0.991475	1.036953
LUAD	SBS31	PLChemotherapy	0.880629	0.799015	0.970579	0.89312	0.790183	1.009466
LUAD	SBS32	AZA Chemotherapy	1.007033	0.917883	1.104841	1.043587	0.915357	1.189779
LUAD	SBS33	Unknown	1.02678	0.989877	1.06506	1.035637	0.996943	1.075834
LUAD	SBS34	Unknown	0.81226	0.55389	1.191149	0.673981	0.367135	1.237284
LUAD	SBS35	PLChemotherapy	0.996923	0.949822	1.046359	0.997416	0.935663	1.063245
LUAD	SBS36	BERrepair MUTY	0.98615	0.935578	1.039456	1.003078	0.920809	1.092697
LUAD	SBS37	Unknown	0.957005	0.772093	1.186203	1.135224	0.840288	1.533679
LUAD	SBS38	UV	1.001168	0.976504	1.026455	1.006324	0.976905	1.036629
LUAD	SBS39	Unknown	1.002066	0.995395	1.008781	1.003181	0.996228	1.010182
LUAD	SBS42	Haloalkane	1.012819	0.988571	1.037662	0.994742	0.962463	1.028103
LUAD	SBS84	Actind cytidinedeaminase	1.052462	0.92855	1.192911	0.864712	0.707477	1.056892
LUAD	SBS40	Unknown	0.957959	0.616794	1.487833	0.980896	0
LUAD	SBS41	Unknown	1.683135	1.069099	2.649842	1269092	0
LUAD	SBS44	Mismatchrepair	0.975844	0.725802	1.312027	0.000283	0
LUAD	SBS85	Actind cytidinedeaminase	0.874298	0.530535	1.440805	0.774711	0.306602	1.957514
LUAD	SBS9	PolETA Somatichypermutati	1.101917	0.890607	1.363363	0.064549	0
LUSC	SBS1	Endogenous clock-like age	0.991197	0.972212	1.010553	0.984712	0.962477	1.007461
LUSC	SBS2	Endogenous Apobec3a	1.002116	0.994994	1.009288	1.001743	0.994346	1.009196
LUSC	SBS3	Homologous repair	0.981184	0.945106	1.018639	0.994945	0.957047	1.034343
LUSC	SBS4	Tobacco	0.999915	0.997553	1.002283	1.000125	0.997639	1.002619
LUSC	SBS6	Mismatchrepair	0.977191	0.953053	1.001942	0.990625	0.957451	1.024949
LUSC	SBS7a	UV	0.999011	0.995636	1.002397	0.999078	0.995373	1.002796
LUSC	SBS7b	UV	0.999776	0.99871	1.000842	0.999733	0.998687	1.000781
LUSC	SBS7c	UV	1.000722	0.967763	1.034804	0.99788	0.962885	1.034146
LUSC	SBS7d	UV	0.955215	0.855547	1.066494	0.956939	0.829583	1.103846
LUSC	SBS8	Unknown	0.966303	0.913224	1.022468	0.967334	0.893988	1.046697
LUSC	SBS10a	Polymerase epsilon hyperm	0.917169	0.815143	1.031965	0.910375	0.761926	1.087746
LUSC	SBS10b	Polymerase epsilon mutati	0.996799	0.974894	1.019195	1.003524	0.979695	1.027932
LUSC	SBS11	Temozolo Chemotherapy	0.957652	0.853616	1.074368	0.893643	0.737044	1.083515
LUSC	SBS12	Liver cancer	1.013032	0.981705	1.045358	1.027458	0.981098	1.076009
LUSC	SBS13	Endogenous apobec	1.00244	0.997299	1.007607	1.002924	0.997736	1.008139
LUSC	SBS14	Mismatchrepair + PolEpsil	0.805816	0.623046	1.042203	0.679011	0.435177	1.059467
LUSC	SBS15	Mismatchrepair	1.001299	0.99961	1.002991	1.001171	0.999406	1.002939
LUSC	SBS16	Unknown	0.989237	0.935955	1.045553	1.009222	0.935091	1.089229
LUSC	SBS17a	Unknown	0.994434	0.929337	1.064091	0.954336	0.874956	1.040917
LUSC	SBS17b	Unknown	0.971889	0.816446	1.156927	1.056452	0.852644	1.308977
LUSC	SBS18	ReactiveOxy	0.996575	0.977836	1.015673	0.985092	0.950933	1.020479
LUSC	SBS19	Unknown	0.992181	0.964026	1.021158	0.979169	0.942723	1.017024
LUSC	SBS21	Mismatchrepair	0.922737	0.840794	1.012666	0.938501	0.83647	1.052977
LUSC	SBS22	Aristolochic acid	0.985895	0.953844	1.019023	0.992384	0.952876	1.03353
LUSC	SBS23	Unknown	0.927624	0.860772	0.999667	0.95831	0.871718	1.053504
LUSC	SBS24	Aflatoxin	0.996118	0.98708	1.00524	1.001943	0.991854	1.012134
LUSC	SBS25	Chemotherapy	0.995339	0.973929	1.01722	0.998174	0.968468	1.028792
LUSC	SBS26	Mismatchrepair	0.991372	0.973456	1.009618	0.99415	0.974549	1.014146
LUSC	SBS28	Unknown	1.05417	0.832317	1.335157	0.963042	0.668381	1.387608
LUSC	SBS29	Tobacco chewing in Hollst	1.009665	0.993695	1.025892	1.003673	0.98054	1.027353
LUSC	SBS20	Mismatchrepair + POLD1mut	0.999913	0.963835	1.037342	0.966365	0.911504	1.024527
LUSC	SBS30	BER repair-NTHL1mut	0.994764	0.976116	1.013769	0.992675	0.968157	1.017814
LUSC	SBS31	PLChemotherapy	1.013935	0.985649	1.043033	1.013578	0.97575	1.052873
LUSC	SBS32	AZA Chemotherapy	0.865466	0.748815	1.000288	0.927943	0.759204	1.134186
LUSC	SBS33	Unknown	0.911796	0.846568	0.982049	0.933154	0.857408	1.015592
LUSC	SBS34	Unknown	0.932865	0.728844	1.193996	0.839489	0.550551	1.280067
LUSC	SBS35	PLChemotherapy	1.002425	0.983206	1.02202	1.003724	0.978672	1.029416
LUSC	SBS36	BERrepair MUTY	0.910768	0.831744	0.9973	0.995861	0.86879	1.141517
LUSC	SBS37	Unknown	1.050847	0.890773	1.239688	0.767181	0.463904	1.268724
LUSC	SBS38	UV	0.999008	0.985563	1.012636	0.993808	0.972651	1.015426
LUSC	SBS39	Unknown	0.994402	0.985831	1.003048	0.996171	0.987439	1.004981
LUSC	SBS42	Haloalkane	0.981875	0.92829	1.038552	0.979814	0.89133	1.077081
LUSC	SBS84	Actind cytidinedeaminase	0.997309	0.886353	1.122156	1.169105	0.876302	1.559745
LUSC	SBS85	Actind cytidinedeaminase	1.096666	0.819327	1.467883	0.616003	0.227812	1.665669
LUSC	SBS40	Unknown	0.786358	0.307482	2.011039
LUSC	SBS41	Unknown	1.285615	0.713674	2.31591	1.43E+43	0
LUSC	SBS44	Mismatchrepair	0.986026	0.906962	1.071982	1.082898	0.833575	1.406793
LUSC	SBS9	PolETA Somatichypermutati	0.989094	0.711043	1.375877	0.006287	0
OV	SBS1	Endogenous clock-like age	1.026547	1.002186	1.0515	1.035567	1.007606	1.064304
OV	SBS2	Endogenous Apobec3a	1.019574	0.985585	1.054735	1.008298	0.967571	1.050739
OV	SBS3	Homologous repair	1.000239	0.997522	1.002963	0.998965	0.996079	1.001859
OV	SBS4	Tobacco	0.996729	0.977392	1.016448	1.00226	0.979532	1.025515
OV	SBS6	Mismatchrepair	1.000951	0.980591	1.021733	1.002916	0.975717	1.030875
OV	SBS7a	UV	0.972344	0.933967	1.012299	1.013818	0.9717	1.057762
OV	SBS7b	UV	0.976475	0.934117	1.020753	0.97733	0.914485	1.044493
OV	SBS7c	UV	1.008435	0.954931	1.064937	1.014038	0.95668	1.074834
OV	SBS7d	UV	1.009564	0.935011	1.090061	1.104863	0.996822	1.224613
OV	SBS8	Unknown	0.979682	0.962208	0.997472	0.973229	0.950479	0.996524
OV	SBS9	PolETA Somatichypermutati	0.958239	0.901071	1.019034	0.939082	0.846986	1.041192
OV	SBS10a	Polymerase epsilon hyperm	1.062548	0.929745	1.21432	1.119132	0.919587	1.361977
OV	SBS10b	Polymerase epsilon mutati	1.046007	0.996088	1.098427	1.042212	0.979108	1.109383
OV	SBS11	Temozolo Chemotherapy	1.004428	0.943991	1.068734	0.94103	0.838699	1.055847
OV	SBS12	Liver cancer	0.954846	0.900589	1.012372	0.943516	0.871163	1.021879
OV	SBS13	Endogenous apobec	0.98256	0.945669	1.02089	1.001315	0.965724	1.038218
OV	SBS14	Mismatchrepair + PolEpsil	0.993476	0.938498	1.051674	0.972651	0.890846	1.061969
OV	SBS15	Mismatchrepair	0.982126	0.948768	1.016656	0.980292	0.93109	1.032094
OV	SBS16	Unknown	1.045553	0.950798	1.149751	0.995799	0.865322	1.145949
OV	SBS17a	Unknown	0.995621	0.947498	1.046189	0.988532	0.933211	1.047133
OV	SBS17b	Unknown	0.918168	0.800724	1.052839	0.942803	0.791266	1.123363
OV	SBS18	ReactiveOxy	0.987752	0.958416	1.017987	0.989893	0.954982	1.02608
OV	SBS19	Unknown	0.983705	0.952404	1.016036	0.970778	0.93068	1.012603
OV	SBS21	Mismatchrepair	1.055729	0.994724	1.120476	1.033488	0.951939	1.122023
OV	SBS22	Aristolochic acid	0.997297	0.979206	1.015722	0.993585	0.9735	1.014084
OV	SBS23	Unknown	1.063841	0.996963	1.135205	1.138545	1.02811	1.260842
OV	SBS24	Aflatoxin	1.002533	0.984043	1.02137	0.992236	0.968158	1.016914
OV	SBS25	Chemotherapy	1.002999	0.990731	1.015418	1.002951	0.986371	1.01981
OV	SBS26	Mismatchrepair	1.011969	0.962424	1.064065	0.999196	0.930109	1.073415
OV	SBS28	Unknown	0.982293	0.90885	1.061671	1.01709	0.933212	1.108506
OV	SBS29	Tobacco chewing in Hollst	0.989912	0.966259	1.014144	1.007941	0.976743	1.040136
OV	SBS20	Mismatchrepair + POLD1mut	1.052289	1.003188	1.103793	1.022647	0.95241	1.098064
OV	SBS30	BER repair-NTHL1mut	1.002949	0.979482	1.026978	0.976205	0.942402	1.01122
OV	SBS31	PLChemotherapy	0.99082	0.951804	1.031436	0.959847	0.898328	1.025578
OV	SBS32	AZA Chemotherapy	0.970858	0.932558	1.010732	0.981582	0.933592	1.032039
OV	SBS33	Unknown	1.030349	0.954861	1.111804	1.074246	0.975028	1.183562
OV	SBS34	Unknown	0.994585	0.861453	1.148292	0.989862	0.819354	1.195854
OV	SBS35	PLChemotherapy	0.991791	0.959978	1.024659	0.982316	0.93678	1.030066
OV	SBS36	BERrepair MUTY	1.003391	0.966368	1.041832	0.992728	0.943637	1.044373
OV	SBS37	Unknown	1.001864	0.987788	1.01614	0.989068	0.970316	1.008182
OV	SBS38	UV	0.977508	0.91017	1.049827	1.016307	0.951359	1.085688
OV	SBS39	Unknown	0.996994	0.990556	1.003474	0.997518	0.990807	1.004274
OV	SBS42	Haloalkane	1.013042	0.981862	1.045213	1.01362	0.973921	1.054938
OV	SBS84	Actind cytidinedeaminase	0.977411	0.934878	1.021879	0.958082	0.896799	1.023553
OV	SBS85	Actind cytidinedeaminase	1.100179	0.984213	1.229809	1.186825	1.015458	1.387112
OV	SBS40	Unknown	1.0142	0.9857	1.043525	1.048542	0.98826	1.112502
OV	SBS41	Unknown	0.875853	0.64972	1.180691	1.619845	0.905561	2.897537
OV	SBS44	Mismatchrepair	1.035501	0.9565	1.121026	1.049874	0.932963	1.181435
PAAD	SBS1	Endogenous clock-like age	1.000308	0.999008	1.001609	1.00035	0.999054	1.001649
PAAD	SBS2	Endogenous Apobec3a	0.977058	0.891669	1.070625	0.994446	0.896192	1.103472
PAAD	SBS3	Homologous repair	0.949877	0.857614	1.052065	1.35E−17	0
PAAD	SBS4	Tobacco	1.047606	0.907042	1.209953	1.068715	0.798265	1.430792
PAAD	SBS6	Mismatchrepair	1.000243	0.999135	1.001353	1.000225	0.999091	1.00136
PAAD	SBS7a	UV	1.009858	0.972562	1.048584	1.009902	0.965433	1.056418
PAAD	SBS7b	UV	1.002183	0.99171	1.012766	1.003706	0.992227	1.015317
PAAD	SBS7c	UV	0.655251	0.405417	1.059043	0.46211	0.18727	1.140313
PAAD	SBS7d	UV	1.004675	0.984211	1.025565	1.012034	0.989024	1.03558
PAAD	SBS8	Unknown	0.606637	0.443697	0.829415	0.4212	0.19977	0.888067
PAAD	SBS9	PolETA Somatichypermutati	0.995163	0.515077	1.922719	0.025783	0
PAAD	SBS10a	Polymerase epsilon hyperm	1.00185	0.993517	1.010253	1.002762	0.993833	1.011772
PAAD	SBS10b	Polymerase epsilon mutati	1.000223	0.99915	1.001297
PAAD	SBS11	Temozolo Chemotherapy	1.000275	0.998978	1.001574	1.000991	0.999202	1.002783
PAAD	SBS12	Liver cancer	0.741179	0.520938	1.054534	0.867836	0.459897	1.637625
PAAD	SBS13	Endogenous apobec	1.009346	0.944524	1.078617	1.00254	0.931542	1.078949
PAAD	SBS14	Mismatchrepair + PolEpsil	1.00011	0.999614	1.000605	1.000064	0.999505	1.000623
PAAD	SBS15	Mismatchrepair	1.000075	0.999745	1.000404	1.000093	0.999758	1.000428
PAAD	SBS16	Unknown	1.04916	0.912364	1.206467	1.033182	0.83459	1.279029
PAAD	SBS17a	Unknown	1.033874	0.967456	1.104852	1.035804	0.962002	1.115268
PAAD	SBS17b	Unknown	1.001553	0.99499	1.008158	1.00086	0.993981	1.007787
PAAD	SBS18	ReactiveOxy	0.974649	0.826597	1.149218	0.722242	0.420651	1.240064
PAAD	SBS19	Unknown	1.000827	0.996916	1.004752	0.99952	0.9953	1.003758
PAAD	SBS21	Mismatchrepair	1.001329	0.994569	1.008134	1.001648	0.994721	1.008623
PAAD	SBS22	Aristolochic acid	0.892572	0.717414	1.110494	0.916449	0.684545	1.226915
PAAD	SBS23	Unknown	1.199069	0.841878	1.707809	1.652299	0.622428	4.386198
PAAD	SBS24	Aflatoxin	1.000522	0.998286	1.002763	1.000487	0.998126	1.002854
PAAD	SBS25	Chemotherapy	1.288326	0.892934	1.858798	2.07779	0.715916	6.030335
PAAD	SBS26	Mismatchrepair	1.000912	0.996958	1.004881	1.000577	0.99643	1.004742
PAAD	SBS28	Unknown	1.003834	0.987779	1.02015	1.011062	0.99112	1.031404
PAAD	SBS29	Tobacco chewing in Hollst	0.998108	0.894236	1.114046	0.977709	0.84216	1.135077
PAAD	SBS20	Mismatchrepair + POLD1mut	1.163218	0.909642	1.487482	1.0696	0.490369	2.333025
PAAD	SBS30	BER repair-NTHL1mut	1.060864	0.925835	1.215586	1.100808	0.896146	1.35221
PAAD	SBS31	PLChemotherapy	0.917579	0.813219	1.035331	0.935442	0.799789	1.094103
PAAD	SBS32	AZA Chemotherapy	0.929344	0.804013	1.074212	0.925429	0.728244	1.176007
PAAD	SBS33	Unknown	1.003129	0.991077	1.015328	1.000665	0.987996	1.013496
PAAD	SBS34	Unknown	1.252467	0.869373	1.804373	1.068736	0.535635	2.132414
PAAD	SBS35	PLChemotherapy	0.930159	0.741202	1.167288	1.07286	0.671546	1.713999
PAAD	SBS36	BERrepair MUTY	0.977949	0.890045	1.074536	1.00396	0.904597	1.114238
PAAD	SBS37	Unknown	0.950492	0.76683	1.178143	0.979141	0.708384	1.353386
PAAD	SBS38	UV	1.151869	0.891832	1.487726	1.421562	0.917286	2.203062
PAAD	SBS39	Unknown	0.976123	0.927275	1.027544	0.983968	0.929601	1.041515
PAAD	SBS39	Unknown	0.976123	0.927275	1.027544	0.983968	0.929601	1.041515
PAAD	SBS42	Haloalkane	1.050143	0.933574	1.181267	0.940761	0.723628	1.223048
PAAD	SBS84	Actind cytidinedeaminase	0.844745	0.564594	1.263908	0.917852	0.305691	2.755893
PAAD	SBS85	Actind cytidinedeaminase	0.624356	0.374393	1.041205	0.443208	0.196912	0.997568
PAAD	SBS40	Unknown
PAAD	SBS41	Unknown	1.119863	0.682336	1.83794
PAAD	SBS44	Mismatchrepair	2.798279	1.627951	4.809952	247.4016	0
SARC	SBS1	Endogenous clock-like age	0.973551	0.941583	1.006604	0.979032	0.94762	1.011484
SARC	SBS2	Endogenous Apobec3a	1.006275	0.914311	1.107488	1.036621	0.918337	1.170139
SARC	SBS3	Homologous repair	0.980775	0.937341	1.026221	0.966239	0.904874	1.031765
SARC	SBS4	Tobacco	0.967859	0.912189	1.026925	1.023179	0.938633	1.115341
SARC	SBS6	Mismatchrepair	0.990295	0.962486	1.018907	0.982674	0.94391	1.023029
SARC	SBS7a	UV	0.999702	0.994377	1.005056	1.000347	0.994822	1.005904
SARC	SBS7b	UV	0.998769	0.99349	1.004077	0.998673	0.993191	1.004186
SARC	SBS7c	UV	0.986183	0.885542	1.098262	0.952487	0.782476	1.159436
SARC	SBS7d	UV	1.052376	0.944387	1.172715	1.015627	0.873974	1.18024
SARC	SBS8	Unknown	0.987133	0.935919	1.04115	0.995939	0.925583	1.071642
SARC	SBS9	PolETA Somatichypermutati	1.23103	0.459378	3.298879	2.21E−22	0
SARC	SBS10a	Polymerase epsilon hyperm	0.829403	0.609755	1.128175	0.730069	0.476857	1.117739
SARC	SBS10b	Polymerase epsilon mutati	1.003002	0.981057	1.025437	0.999975	0.976401	1.024118
SARC	SBS11	Temozolo Chemotherapy	0.881941	0.686403	1.133184	0.977215	0.826929	1.154815
SARC	SBS12	Liver cancer	0.897838	0.766852	1.051197	0.920545	0.744599	1.138067
SARC	SBS13	Endogenous apobec	0.999318	0.917641	1.088264	0.998889	0.902372	1.105729
SARC	SBS14	Mismatchrepair + PolEpsil	0.996877	0.960627	1.034495	1.015868	0.975552	1.057851
SARC	SBS15	Mismatchrepair	0.983507	0.953511	1.014446	0.975408	0.936097	1.01637
SARC	SBS16	Unknown	1.028424	0.928973	1.138522	0.991221	0.862906	1.138618
SARC	SBS17a	Unknown	1.032515	0.889679	1.198283	1.063697	0.867025	1.30498
SARC	SBS17b	Unknown	1.039433	0.823582	1.311855	0.928609	0.632929	1.362419
SARC	SBS18	ReactiveOxy	0.938258	0.849096	1.036782	0.854824	0.711896	1.026448
SARC	SBS19	Unknown	0.974241	0.901617	1.052715	0.910728	0.816875	1.015365
SARC	SBS21	Mismatchrepair	1.026451	0.922344	1.142309	1.040077	0.908358	1.190895
SARC	SBS22	Aristolochic acid	1.077994	0.967668	1.200898	1.002737	0.868528	1.157685
SARC	SBS23	Unknown	0.969069	0.853962	1.099692	0.983232	0.867658	1.114202
SARC	SBS24	Aflatoxin	0.999878	0.993007	1.006796	0.998041	0.990604	1.005534
SARC	SBS25	Chemotherapy	0.941342	0.791624	1.119377	0.700656	0.487185	1.007662
SARC	SBS26	Mismatchrepair	0.978155	0.908214	1.053481	0.96666	0.870857	1.073002
SARC	SBS28	Unknown	0.865281	0.639532	1.170718	0.587387	0.344842	1.000526
SARC	SBS29	Tobacco chewing in Hollst	1.000152	0.996255	1.004064	1.000371	0.996413	1.004344
SARC	SBS20	Mismatchrepair + POLD1mut	0.889346	0.76424	1.034932	0.924094	0.783693	1.089647
SARC	SBS30	BER repair-NTHL1mut	0.980348	0.921733	1.042691	0.906729	0.818296	1.00472
SARC	SBS31	PLChemotherapy	0.989043	0.931688	1.049929	0.980488	0.893957	1.075395
SARC	SBS32	AZA Chemotherapy	1.006805	0.930258	1.089649	1.002456	0.901251	1.115025
SARC	SBS33	Unknown	0.957552	0.825938	1.110139	0.908553	0.75044	1.09998
SARC	SBS34	Unknown	1.047167	0.851128	1.288359	1.019586	0.772677	1.345394
SARC	SBS35	PLChemotherapy	0.972011	0.898209	1.051878	0.998324	0.882867	1.12888
SARC	SBS36	BERrepair MUTY	0.964235	0.827517	1.12354	1.079063	0.860702	1.352822
SARC	SBS37	Unknown	1.055725	0.926602	1.202842	1.192635	0.990338	1.436256
SARC	SBS38	UV	1.01599	0.908242	1.136519	0.973787	0.840105	1.128741
SARC	SBS39	Unknown	1.006254	0.986264	1.02665	0.998671	0.975625	1.022261
SARC	SBS42	Haloalkane	1.002868	0.936394	1.074061	0.940316	0.821666	1.076099
SARC	SBS84	Actind cytidinedeaminase	1.0163	0.907792	1.137777	0.8868	0.747675	1.051812
SARC	SBS85	Actind cytidinedeaminase	0.989763	0.826954	1.184625	1.126438	0.874323	1.45125
SARC	SBS40	Unknown	2.07E−12	0
SARC	SBS41	Unknown	0.878728	0.529646	1.457885	1.271401	0.263818	6.127176
SARC	SBS44	Mismatchrepair	0.951682	0.798427	1.134354	0.803833	0.572206	1.129222
SKCM	SBS1	Endogenous clock-like age	0.995727	0.988513	1.002994	0.995138	0.987531	1.002805
SKCM	SBS2	Endogenous Apobec3a	1.007317	0.951673	1.066215	0.982693	0.90373	1.068556
SKCM	SBS3	Homologous repair	1.020191	0.952978	1.092145	2.964196	0
SKCM	SBS4	Tobacco	1.085466	0.993805	1.185581	0.931244	0.763038	1.136529
SKCM	SBS6	Mismatchrepair	0.996585	0.990153	1.003058	0.998257	0.990992	1.005575
SKCM	SBS7a	UV	0.999873	0.999532	1.000215	0.999931	0.999606	1.000257
SKCM	SBS7b	UV	0.999909	0.999519	1.000299	1.000004	0.999627	1.000382
SKCM	SBS7c	UV	1.002825	0.991115	1.014672	1.011962	1.000373	1.023684
SKCM	SBS7d	UV	1.010144	0.996953	1.023511	0.998622	0.981604	1.015936
SKCM	SBS8	Unknown	1.235565	1.040072	1.467803	0.944396	0.28424	3.137784
SKCM	SBS9	PolETA Somatichypermutati	0.794081	0.419331	1.503739
SKCM	SBS10a	Polymerase epsilon hyperm	1.244704	0.895085	1.730884	0.823255	0.408301	1.659924
SKCM	SBS10b	Polymerase epsilon mutati	0.999652	0.998395	1.000912	0.999783	0.998622	1.000945
SKCM	SBS11	Temozolo Chemotherapy	0.981869	0.950241	1.01455	0.953015	0.903699	1.005022
SKCM	SBS12	Liver cancer	1.078386	0.995296	1.168412	1.174069	1.002716	1.374703
SKCM	SBS13	Endogenous apobec	1.047665	0.999467	1.098188	1.025301	0.971211	1.082403
SKCM	SBS14	Mismatchrepair + PolEpsil	0.803129	0.474407	1.359626	1.03E+53	0
SKCM	SBS15	Mismatchrepair	0.988826	0.949756	1.029503	0.960557	0.897608	1.027922
SKCM	SBS16	Unknown	1.133231	0.983867	1.30527	1.00431	0.771887	1.306719
SKCM	SBS17a	Unknown	0.966045	0.916508	1.018259	0.995243	0.971276	1.019801
SKCM	SBS17b	Unknown	0.988705	0.924904	1.056907	0.924369	0.836819	1.021077
SKCM	SBS18	ReactiveOxy	1.0129	0.93634	1.09572	0.983224	0.871123	1.10975
SKCM	SBS19	Unknown	0.99158	0.974876	1.008569	0.990005	0.965821	1.014794
SKCM	SBS21	Mismatchrepair	0.980838	0.955134	1.007234	0.964277	0.927724	1.00227
SKCM	SBS22	Aristolochic acid	1.003296	0.974005	1.033468	1.007038	0.974953	1.040179
SKCM	SBS23	Unknown	0.999531	0.997072	1.001997	0.999078	0.995074	1.003098
SKCM	SBS24	Aflatoxin	0.979254	0.912727	1.05063	0.980141	0.896045	1.072128
SKCM	SBS25	Chemotherapy	1.666475	1.24918	2.22317	1309566	0
SKCM	SBS26	Mismatchrepair	0.99383	0.980529	1.007312	0.993613	0.979733	1.00769
SKCM	SBS28	Unknown	0.974599	0.838795	1.132391	0.915381	0.490351	1.708819
SKCM	SBS29	Tobacco chewing in Hollst	0.942453	0.780662	1.137774	0.753478	0.449907	1.261882
SKCM	SBS20	Mismatchrepair + POLD1mut	0.987338	0.958315	1.01724	0.982958	0.945845	1.021528
SKCM	SBS30	BER repair-NTHL1mut	1.001028	0.988601	1.013611	0.993016	0.973703	1.012711
SKCM	SBS31	PLChemotherapy	0.999852	0.998831	1.000873	0.999616	0.998107	1.001128
SKCM	SBS32	AZA Chemotherapy	0.99437	0.878381	1.125675	0.965483	0.766523	1.216086
SKCM	SBS33	Unknown	0.980622	0.917976	1.047542	0.976696	0.898499	1.061699
SKCM	SBS34	Unknown	1.332761	1.063535	1.670141	1.799314	1.073199	3.01671
SKCM	SBS35	PLChemotherapy	1.004549	0.983047	1.026522	1.000918	0.972648	1.03001
SKCM	SBS36	BERrepair MUTY	1.1778	1.002803	1.383335	1.10942	0.388859	3.165191
SKCM	SBS37	Unknown	1.138753	0.965761	1.342733	1.118885	0.773813	1.617838
SKCM	SBS38	UV	1.011944	0.996484	1.027643	1.010425	0.994397	1.026712
SKCM	SBS39	Unknown	0.986111	0.960546	1.012356	0.986395	0.94962	1.024593
SKCM	SBS42	Haloalkane	1.003413	0.987152	1.019941	1.011465	0.986412	1.037153
SKCM	SBS84	Actind cytidinedeaminase	0.986729	0.930257	1.046629	0.946763	0.859676	1.042672
SKCM	SBS85	Actind cytidinedeaminase	0.959734	0.661735	1.39193	1.49E−24	0
SKCM	SBS40	Unknown	2.612563	1.348941	5.059883
SKCM	SBS40	Unknown	2.612563	1.348941	5.059883
SKCM	SBS41	Unknown
SKCM	SBS44	Mismatchrepair	1.029959	0.864713	1.226784	2.84E−06	0
STAD	SBS1	Endogenous clock-like age	0.998901	0.997146	1.000659	0.998899	0.997142	1.000659
STAD	SBS2	Endogenous Apobec3a	0.971352	0.922956	1.022286	0.956455	0.898556	1.018084
STAD	SBS3	Homologous repair	0.992333	0.960352	1.025379	0.892345	0.778376	1.023002
STAD	SBS4	Tobacco	0.987137	0.961887	1.013051	0.971933	0.938014	1.007079
STAD	SBS6	Mismatchrepair	0.99911	0.997626	1.000596	0.999331	0.99792	1.000743
STAD	SBS7a	UV	0.995297	0.971358	1.019826	0.973097	0.927417	1.021028
STAD	SBS7b	UV	0.970953	0.940827	1.002043	0.974094	0.937994	1.011584
STAD	SBS7c	UV	0.971589	0.88419	1.067627	0.899012	0.727125	1.111532
STAD	SBS7d	UV	1.030698	0.942751	1.126849	1.03295	0.911852	1.170131
STAD	SBS8	Unknown	0.997723	0.979371	1.01642	0.980256	0.926685	1.036924
STAD	SBS9	PolETA Somatichypermutati	1.00876	0.947686	1.073769	0.146026	0.002307	9.241957
STAD	SBS10a	Polymerase epsilon hyperm	0.989573	0.956765	1.023505	0.970762	0.917416	1.02721
STAD	SBS10b	Polymerase epsilon mutati	0.98786	0.970046	1.006002	0.988042	0.96914	1.007312
STAD	SBS11	Temozolo Chemotherapy	1.001179	0.974131	1.028978	0.989673	0.954066	1.02661
STAD	SBS12	Liver cancer	1.051807	0.981704	1.126916	1.075033	0.951365	1.214776
STAD	SBS13	Endogenous apobec	0.978181	0.938827	1.019183	0.970983	0.924447	1.019861
STAD	SBS14	Mismatchrepair + PolEpsil	0.995019	0.981213	1.009019	0.997018	0.986775	1.007367
STAD	SBS15	Mismatchrepair	0.998327	0.996289	1.00037	0.997682	0.995244	1.000127
STAD	SBS16	Unknown	0.857398	0.734335	1.001083	0.794443	0.630406	1.001164
STAD	SBS17a	Unknown	0.998227	0.988111	1.008446	0.99821	0.987751	1.00878
STAD	SBS17b	Unknown	0.998204	0.992534	1.003907	0.998707	0.9931	1.004346
STAD	SBS18	ReactiveOxy	0.995935	0.964147	1.02877	0.97967	0.931476	1.030357
STAD	SBS19	Unknown	0.975866	0.909581	1.046982	0.984795	0.881151	1.10063
STAD	SBS21	Mismatchrepair	0.993796	0.981541	1.006203	0.993398	0.980064	1.006913
STAD	SBS22	Aristolochic acid	1.021431	0.997016	1.046444	1.014278	0.984263	1.045207
STAD	SBS23	Unknown	0.92551	0.761899	1.124256	0.45891	0.122634	1.7173
STAD	SBS24	Aflatoxin	0.992398	0.955156	1.031092	0.98445	0.934041	1.03758
STAD	SBS25	Chemotherapy	0.998529	0.979856	1.017558	1.010175	0.988049	1.032796
STAD	SBS26	Mismatchrepair	0.997992	0.99493	1.001063	0.997996	0.994409	1.001595
STAD	SBS28	Unknown	0.994152	0.97748	1.011108	0.989785	0.968249	1.011799
STAD	SBS29	Tobacco chewing in Hollst	0.975695	0.949437	1.002679	0.975706	0.943531	1.008977
STAD	SBS20	Mismatchrepair + POLD1mut	1.000739	0.995879	1.005623	1.0026	0.996834	1.008398
STAD	SBS30	BER repair-NTHL1mut	1.008145	0.976994	1.04029	1.008054	0.972069	1.045372
STAD	SBS31	PLChemotherapy	0.984231	0.923245	1.049247	1.030515	0.927195	1.145349
STAD	SBS32	AZA Chemotherapy	0.986463	0.907148	1.072713	0.965213	0.816452	1.141079
STAD	SBS33	Unknown	0.986455	0.967408	1.005877	0.987885	0.966946	1.009276
STAD	SBS34	Unknown	0.925416	0.744717	1.14996	0.978913	0.86828	1.103642
STAD	SBS35	PLChemotherapy	0.994701	0.97418	1.015653	0.990998	0.965227	1.017457
STAD	SBS36	BERrepair MUTY	1.012284	0.967223	1.059444	0.978849	0.878056	1.091213
STAD	SBS37	Unknown	0.98521	0.939327	1.033335	0.988056	0.938906	1.03978
STAD	SBS38	UV	0.995902	0.935194	1.060549	0.954404	0.868693	1.048572
STAD	SBS39	Unknown	0.99859	0.98752	1.009783	0.996021	0.983212	1.008996
STAD	SBS42	Haloalkane	0.996431	0.978298	1.014901	0.992876	0.963576	1.023068
STAD	SBS84	Actind cytidinedeaminase	0.979075	0.846973	1.131781	0.775513	0.530736	1.133181
STAD	SBS85	Actind cytidinedeaminase	1.087161	0.930772	1.269826	1.175035	0.921103	1.498971
STAD	SBS40	Unknown	0.969256	0.745995	1.259336	2.01977	0
STAD	SBS41	Unknown	1.217248	0.631382	2.346744	2100833	0
STAD	SBS44	Mismatchrepair	1.074344	0.913053	1.264128	44938.89	0
UCEC	SBS1	Endogenous clock-like age	0.995467	0.991641	0.999307	0.995209	0.991248	0.999186
UCEC	SBS2	Endogenous Apobec3a	0.994485	0.980144	1.009035	0.991268	0.97544	1.007353
UCEC	SBS3	Homologous repair	1.014477	0.987944	1.041722	1.045252	0.96913	1.127353
UCEC	SBS4	Tobacco	0.990057	0.968272	1.012333	0.975279	0.946449	1.004987
UCEC	SBS6	Mismatchrepair	0.996574	0.993968	0.999187	0.995398	0.992427	0.998378
UCEC	SBS7a	UV	0.99096	0.967533	1.014955	0.985487	0.95348	1.018569
UCEC	SBS7c	UV	0.888251	0.746444	1.056999	0.833505	0.616844	1.126266
UCEC	SBS7d	UV	0.95721	0.870652	1.052375	0.858818	0.686921	1.07373
UCEC	SBS8	Unknown	0.992802	0.959066	1.027725	0.948798	0.86254	1.043683
UCEC	SBS9	PolETA Somatichypermutati	0.55147	0.104898	2.899178	1.126085	0
UCEC	SBS10a	Polymerase epsilon hyperm	0.998561	0.996714	1.000411	0.998567	0.996686	1.000451
UCEC	SBS10b	Polymerase epsilon mutati	0.999362	0.998657	1.000067	0.999342	0.998612	1.000072
UCEC	SBS11	Temozolo Chemotherapy	0.936609	0.812414	1.079789	0.916964	0.731692	1.14915
UCEC	SBS12	Liver cancer	0.993322	0.938705	1.051117	0.96023	0.856154	1.076958
UCEC	SBS13	Endogenous apobec	0.999398	0.992411	1.006433	0.997728	0.98987	1.005649
UCEC	SBS14	Mismatchrepair + PolEpsil	0.99853	0.996638	1.000425	0.998859	0.997174	1.000546
UCEC	SBS15	Mismatchrepair	0.999791	0.99941	1.000173	0.999889	0.999518	1.00026
UCEC	SBS16	Unknown	1.02735	0.930914	1.133777	0.887607	0.761484	1.034618
UCEC	SBS17a	Unknown	0.892296	0.805733	0.98816	0.896752	0.80032	1.004804
UCEC	SBS17b	Unknown	0.994908	0.988296	1.001565	0.99653	0.98972	1.003385
UCEC	SBS18	ReactiveOxy	1.019476	0.985387	1.054745	0.994023	0.952547	1.037304
UCEC	SBS19	Unknown	0.989805	0.954641	1.026264	0.988714	0.950701	1.028246
UCEC	SBS21	Mismatchrepair	0.99977	0.998522	1.001019	0.999979	0.998994	1.000964
UCEC	SBS22	Aristolochic acid	0.999413	0.974255	1.02522	0.99367	0.958971	1.029623
UCEC	SBS23	Unknown	0.972301	0.903334	1.046534	0.936475	0.813924	1.077478
UCEC	SBS24	Aflatoxin	0.991306	0.960077	1.02355	0.968558	0.912413	1.028159
UCEC	SBS25	Chemotherapy	0.882337	0.634653	1.226683	1.337783	0
UCEC	SBS26	Mismatchrepair	0.998553	0.996334	1.000776	0.999091	0.997096	1.00109
UCEC	SBS28	Unknown	0.992082	0.980096	1.004214	0.993107	0.981524	1.004827
UCEC	SBS29	Tobacco chewing in Hollst	0.99381	0.972217	1.015883	0.973283	0.914564	1.035772
UCEC	SBS20	Mismatchrepair + POLD1mut	0.991606	0.983384	0.999896	0.986656	0.975949	0.99748
UCEC	SBS30	BER repair-NTHL1mut	0.996595	0.981031	1.012407	0.998	0.980323	1.015995
UCEC	SBS31	PLChemotherapy	0.971295	0.917214	1.028565	0.962298	0.879176	1.05328
UCEC	SBS32	AZA Chemotherapy	0.968769	0.913472	1.027413	0.95524	0.8574	1.064244
UCEC	SBS33	Unknown	0.984489	0.971748	0.997397	0.982756	0.968183	0.997549
UCEC	SBS34	Unknown	1.000831	0.915302	1.094352	0.949446	0.820885	1.098142
UCEC	SBS35	PLChemotherapy	0.977475	0.886352	1.077967	0.944967	0.822044	1.08627
UCEC	SBS36	BERrepair MUTY	0.985029	0.95606	1.014876	0.973866	0.924938	1.025382
UCEC	SBS37	Unknown	0.99463	0.986653	1.002671	0.989674	0.979168	1.000294
UCEC	SBS38	UV	0.878331	0.770314	1.001494	0.816338	0.667022	0.99908
UCEC	SBS39	Unknown	1.009658	0.994202	1.025354	1.002954	0.984291	1.021971
UCEC	SBS42	Haloalkane	0.99158	0.968823	1.014872	0.971814	0.924512	1.021537
UCEC	SBS84	Actind cytidinedeaminase	0.9926	0.973836	1.011725	0.984446	0.952453	1.017513
UCEC	SBS85	Actind cytidinedeaminase	0.91697	0.710587	1.183295	0.901636	0.649506	1.25164
UCEC	SBS40	Unknown	0.0003	0
UCEC	SBS41	Unknown	1.023469	0.727377	1.44009	3.5E−10	0
UCEC	SBS44	Mismatchrepair	0.990952	0.972496	1.009757	0.985118	0.957295	1.013751
UCEC	SBS7b	UV	0.997693	0.993565	1.001838	0.997015	0.992301	1.001751
Absence of data indicates that models did not converge, usually due to small cell sizes.
indicates data missing or illegible when filed

TABLE 2B
Mutational signatures related to disease-specific survival (DSS), according to each cancer. Restricted to cancers with DSS events > n = 50, and binary cutpoints with cell sizes > n = 5.

Dichotomous (maxstat) signature results

Below

cut-

Below

point

cut-

no

point

Signature

Percent

Percent

Percent

event

event

Signature

no event

no sig

no sig

Percent

Sig no

Hazard

Cancer

Sig

Signature Label

(n)

(n)

event (n)

(n)

no event

event

sig event

event

Ratio

HRLowerCL

HRUpperCL

BLCA	SBS1	Endogenous clock-like age	203	103	20	69	0.746324	0.837398	0.162602	0.253676	0.500134	0.308728	0.810209
BLCA	SBS2	Endogenous Apobec3a	84	64	59	188	0.308824	0.520325	0.479675	0.691176	0.447284	0.31223	0.640756
BLCA	SBS4	Tobacco	219	93	30	53	0.805147	0.756098	0.243902	0.194853	1.111636	0.733305	1.685158
BLCA	SBS6	Mismatchrepair	227	107	16	45	0.834559	0.869919	0.130081	0.165441	0.800584	0.471745	1.358647
BLCA	SBS7a	UV	191	107	16	81	0.702206	0.869919	0.130081	0.297794	0.355418	0.208379	0.606213
BLCA	SBS7b	UV	209	83	40	63	0.768382	0.674797	0.325203	0.231618	1.647018	1.122438	2.416764
BLCA	SBS7c	UV	237	102	21	35	0.871324	0.829268	0.170732	0.128676	1.253245	0.780568	2.012155
BLCA	SBS7d	UV	242	110	13	30	0.889706	0.894309	0.105691	0.110294	1.128211	0.633784	2.008352
BLCA	SBS10a	Polymerase epsilon hyperm	229	96	27	43	0.841912	0.780488	0.219512	0.158088	1.682185	1.091556	2.592398
BLCA	SBS10b	Polymerase epsilon mutati
BLCA	SBS12	Liver cancer	240	110	13	32	0.882353	0.894309	0.105691	0.117647	0.740546	0.414625	1.322661
BLCA	SBS13	Endogenous apobec	115	75	48	157	0.422794	0.609756	0.390244	0.577206	0.462315	0.318989	0.67004
BLCA	SBS14	Mismatchrepair + PolEpsil	245	106	17	27	0.900735	0.861789	0.138211	0.099265	1.233865	0.738066	2.062719
BLCA	SBS15	Mismatchrepair	225	97	26	47	0.827206	0.788618	0.211382	0.172794	1.16743	0.754804	1.805623
BLCA	SBS16	Unknown	235	114	9	37	0.863971	0.926829	0.073171	0.136029	0.548239	0.275888	1.089448
BLCA	SBS17a	Unknown	242	112	11	30	0.889706	0.910569	0.089431	0.110294	0.765842	0.411188	1.42639
BLCA	SBS17b	Unknown	234	99	24	38	0.860294	0.804878	0.195122	0.139706	1.545177	0.982165	2.430927
BLCA	SBS18	ReactiveOxy	246	108	15	26	0.904412	0.878049	0.121951	0.095588	1.425972	0.828002	2.455787
BLCA	SBS19	Unknown	237	112	11	35	0.871324	0.910569	0.089431	0.128676	0.671418	0.360137	1.251753
BLCA	SBS20	Mismatchrepair + POLD1mut	230	109	14	42	0.845588	0.886179	0.113821	0.154412	0.681349	0.389441	1.19206
BLCA	SBS21	Mismatchrepair	248	106	17	24	0.911765	0.861789	0.138211	0.088235	1.540263	0.920428	2.577508
BLCA	SBS22	Aristolochic acid	227	116	7	45	0.834559	0.943089	0.056911	0.165441	0.33395	0.15537	0.717784
BLCA	SBS23	Unknown	248	99	24	24	0.911765	0.804878	0.195122	0.088235	2.038393	1.301161	3.193338
BLCA	SBS24	Aflatoxin	232	113	10	40	0.852941	0.918699	0.081301	0.147059	0.459174	0.239295	0.881093
BLCA	SBS25	Chemotherapy
BLCA	SBS26	Mismatchrepair	213	104	19	59	0.783088	0.845528	0.154472	0.216912	0.559117	0.34087	0.917098
BLCA	SBS28	Unknown
BLCA	SBS29	Tobacco chewing in Hollst	194	82	41	78	0.713235	0.666667	0.333333	0.286765	1.172878	0.80476	1.709383
BLCA	SBS3	Homologous repair
BLCA	SBS30	BER repair-NTHL1mut	172	64	59	100	0.632353	0.520325	0.479675	0.367647	1.500981	1.051488	2.142624
BLCA	SBS31	PLChemotherapy	238	105	18	34	0.875	0.853659	0.146341	0.125	1.57316	0.950248	2.604407
BLCA	SBS32	AZA Chemotherapy	248	106	17	24	0.911765	0.861789	0.138211	0.088235	1.182944	0.706031	1.982003
BLCA	SBS33	Unknown	166	65	58	106	0.610294	0.528455	0.471545	0.389706	1.246852	0.868093	1.790867
BLCA	SBS34	Unknown	249	104	19	23	0.915441	0.845528	0.154472	0.084559	1.638554	0.998195	2.689713
BLCA	SBS35	PLChemotherapy	241	110	13	31	0.886029	0.894309	0.105691	0.113971	0.812631	0.454475	1.453039
BLCA	SBS36	BERrepair MUTY	240	114	9	32	0.882353	0.926829	0.073171	0.117647	0.520606	0.262945	1.030749
BLCA	SBS38	UV	165	82	41	107	0.606618	0.666667	0.333333	0.393382	0.793306	0.544025	1.156813
BLCA	SBS39	Unknown	119	66	57	153	0.4375	0.536585	0.463415	0.5625	0.607056	0.420714	0.875935
BLCA	SBS42	Haloalkane	246	105	18	26	0.904412	0.853659	0.146341	0.095588	1.205448	0.729594	1.99166
BLCA	SBS11	Temozolo Chemotherapy
BLCA	SBS37	Unknown
BLCA	SBS40	Unknown
BLCA	SBS41	Unknown
BLCA	SBS44	Mismatchrepair
BLCA	SBS8	Unknown
BLCA	SBS84	Actind cytidinedeaminase
BLCA	SBS85	Actind cytidinedeaminase
BLCA	SBS9	PolETA Somatichypermutation
BRCA	SBS1	Endogenous clock-like age	707	57	15	157	0.818287	0.791667	0.208333	0.181713	1.671837	0.925279	3.020752
BRCA	SBS2	Endogenous Apobec3a	759	59	13	105	0.878472	0.819444	0.180556	0.121528	1.670649	0.911221	3.062995
BRCA	SBS4	Tobacco	718	54	18	146	0.831019	0.75	0.25	0.168981	1.619767	0.945909	2.773678
BRCA	SBS6	Mismatchrepair	697	50	22	167	0.806713	0.694444	0.305556	0.193287	1.765044	1.056703	2.948208
BRCA	SBS7a	UV	455	42	30	409	0.52662	0.583333	0.416667	0.47338	0.840224	0.520727	1.355752
BRCA	SBS7b	UV	590	52	20	274	0.68287	0.722222	0.277778	0.31713	0.760819	0.451156	1.283027
BRCA	SBS7c	UV	713	56	16	151	0.825231	0.777778	0.222222	0.174769	1.000099	0.570492	1.753219
BRCA	SBS7d	UV	632	48	24	232	0.731481	0.666667	0.333333	0.268519	1.264394	0.770186	2.07572
BRCA	SBS8	Unknown	744	59	13	120	0.861111	0.819444	0.180556	0.138889	1.265571	0.690079	2.320995
BRCA	SBS10a	Polymerase epsilon hyperm	652	50	22	212	0.75463	0.694444	0.305556	0.24537	1.211663	0.730778	2.008991
BRCA	SBS10b	Polymerase epsilon mutati	768	56	16	96	0.888889	0.777778	0.222222	0.111111	2.726796	1.543688	4.816658
BRCA	SBS11	Temozolo Chemotherapy	762	63	9	102	0.881944	0.875	0.125	0.118056	1.305714	0.644407	2.645671
BRCA	SBS12	Liver cancer	678	56	16	186	0.784722	0.777778	0.222222	0.215278	1.100833	0.626255	1.935046
BRCA	SBS13	Endogenous apobec	411	26	46	453	0.475694	0.361111	0.638889	0.524306	1.544854	0.953315	2.503447
BRCA	SBS14	Mismatchrepair + PolEpsil	765	66	6	99	0.885417	0.916667	0.083333	0.114583	0.526563	0.225339	1.230448
BRCA	SBS15	Mismatchrepair	781	59	13	83	0.903935	0.819444	0.180556	0.096065	1.483161	0.807085	2.725568
BRCA	SBS16	Unknown	703	65	7	161	0.813657	0.902778	0.097222	0.186343	0.591673	0.269963	1.296756
BRCA	SBS17a	Unknown	547	42	30	317	0.633102	0.583333	0.416667	0.366898	1.175573	0.734358	1.881878
BRCA	SBS17b	Unknown	613	58	14	251	0.709491	0.805556	0.194444	0.290509	0.618313	0.343538	1.112864
BRCA	SBS18	ReactiveOxy	732	56	16	132	0.847222	0.777778	0.222222	0.152778	1.668587	0.940123	2.961507
BRCA	SBS19	Unknown	596	45	27	268	0.689815	0.625	0.375	0.310185	1.107766	0.685095	1.791204
BRCA	SBS21	Mismatchrepair	651	60	12	213	0.753472	0.833333	0.166667	0.246528	0.722583	0.383007	1.363231
BRCA	SBS22	Aristolochic acid	707	55	17	157	0.818287	0.763889	0.236111	0.181713	1.678556	0.948967	2.969069
BRCA	SBS23	Unknown	772	66	6	92	0.893519	0.916667	0.083333	0.106481	0.8616	0.371711	1.997131
BRCA	SBS24	Aflatoxin	658	49	23	206	0.761574	0.680556	0.319444	0.238426	1.745965	1.057609	2.882343
BRCA	SBS25	Chemotherapy	835	69	3	29	0.966435	0.958333	0.041667	0.033565	1.120325	0.350805	3.577852
BRCA	SBS26	Mismatchrepair	780	60	12	84	0.902778	0.833333	0.166667	0.097222	1.158786	0.598884	2.242144
BRCA	SBS28	Unknown	717	62	10	147	0.829861	0.861111	0.138889	0.170139	0.832043	0.423866	1.633288
BRCA	SBS29	Tobacco chewing in Hollst	779	61	11	85	0.90162	0.847222	0.152778	0.09838	1.435307	0.746296	2.760443
BRCA	SBS20	Mismatchrepair + POLD1mut	779	57	15	85	0.90162	0.791667	0.208333	0.09838	3.251012	1.815949	5.82014
BRCA	SBS30	BER repair-NTHL1mut	782	59	13	82	0.905093	0.819444	0.180556	0.094907	2.592347	1.404604	4.784456
BRCA	SBS31	PLChemotherapy	743	63	9	121	0.859954	0.875	0.125	0.140046	0.726132	0.359035	1.468569
BRCA	SBS32	AZA Chemotherapy	705	52	20	159	0.815972	0.722222	0.277778	0.184028	1.694012	1.007724	2.847681
BRCA	SBS33	Unknown	697	55	17	167	0.806713	0.763889	0.236111	0.193287	1.43617	0.83083	2.482559
BRCA	SBS34	Unknown	706	64	8	158	0.81713	0.888889	0.111111	0.18287	0.577464	0.275265	1.211434
BRCA	SBS35	PLChemotherapy	738	65	7	126	0.854167	0.902778	0.097222	0.145833	0.750467	0.34274	1.643228
BRCA	SBS36	BERrepair MUTY	736	56	16	128	0.851852	0.777778	0.222222	0.148148	1.709485	0.973319	3.002446
BRCA	SBS37	Unknown	765	57	15	99	0.885417	0.791667	0.208333	0.114583	1.696127	0.955643	3.010377
BRCA	SBS38	UV	753	67	5	111	0.871528	0.930556	0.069444	0.128472	0.577722	0.231411	1.442293
BRCA	SBS39	Unknown	309	17	55	555	0.357639	0.236111	0.763889	0.642361	1.912283	1.107939	3.300568
BRCA	SBS42	Haloalkane	776	64	8	88	0.898148	0.888889	0.111111	0.101852	1.297534	0.615474	2.735443
BRCA	SBS84	Actind cytidinedeaminase	763	69	3	101	0.883102	0.958333	0.041667	0.116898	0.355439	0.111301	1.135091
BRCA	SBS85	Actind cytidinedeaminase	766	61	11	98	0.886574	0.847222	0.152778	0.113426	1.375165	0.716263	2.640202
BRCA	SBS3	Homologous repair
BRCA	SBS40	Unknown
BRCA	SBS41	Unknown
BRCA	SBS44	Mismatchrepair
BRCA	SBS9	PolETA Somatichypermutation
CESC	SBS1	Endogenous clock-like age	152	43	7	66	0.697248	0.86	0.14	0.302752	0.33667	0.14965	0.75741
CESC	SBS2	Endogenous Apobec3a	90	26	24	128	0.412844	0.52	0.48	0.587156	0.56009	0.313478	1.000711
CESC	SBS4	Tobacco	196	43	7	22	0.899083	0.86	0.14	0.100917	1.568587	0.702505	3.502413
CESC	SBS6	Mismatchrepair	109	27	23	109	0.5	0.54	0.46	0.5	0.644357	0.359813	1.15392
CESC	SBS7a	UV	86	30	20	132	0.394495	0.6	0.4	0.605505	0.410394	0.228508	0.737055
CESC	SBS7b	UV	159	41	9	59	0.729358	0.82	0.18	0.270642	0.606398	0.293031	1.254882
CESC	SBS7c	UV	181	35	15	37	0.830275	0.7	0.3	0.169725	1.841501	1.003131	3.380539
CESC	SBS7d	UV	174	45	5	44	0.798165	0.9	0.1	0.201835	0.467003	0.183028	1.191577
CESC	SBS8	Unknown	199	41	9	19	0.912844	0.82	0.18	0.087156	2.058085	0.98344	4.30704
CESC	SBS10a	Polymerase epsilon hyperm	194	42	8	24	0.889908	0.84	0.16	0.110092	1.377072	0.634278	2.989742
CESC	SBS10b	Polymerase epsilon mutati	51	18	32	167	0.233945	0.36	0.64	0.766055	0.534829	0.295725	0.967256
CESC	SBS11	Temozolo Chemotherapy	202	49	1	16	0.926606	0.98	0.02	0.073394	0.324114	0.044589	2.355964
CESC	SBS12	Liver cancer	196	44	6	22	0.899083	0.88	0.12	0.100917	1.537821	0.644753	3.667903
CESC	SBS13	Endogenous apobec	19	7	43	199	0.087156	0.14	0.86	0.912844	0.477991	0.209678	1.089647
CESC	SBS14	Mismatchrepair + PolEpsil	194	44	6	24	0.889908	0.88	0.12	0.110092	1.145838	0.485913	2.702013
CESC	SBS15	Mismatchrepair	176	37	13	42	0.807339	0.74	0.26	0.192661	1.562742	0.810806	3.012021
CESC	SBS16	Unknown	182	41	9	36	0.834862	0.82	0.18	0.165138	0.920772	0.443641	1.911056
CESC	SBS17a	Unknown	179	31	19	39	0.821101	0.62	0.38	0.178899	1.983216	1.096375	3.587411
CESC	SBS17b	Unknown	191	38	12	27	0.876147	0.76	0.24	0.123853	2.038495	1.057252	3.930437
CESC	SBS18	ReactiveOxy	191	43	7	27	0.876147	0.86	0.14	0.123853	1.231324	0.549181	2.760764
CESC	SBS19	Unknown	189	42	8	29	0.866972	0.84	0.16	0.133028	1.327226	0.618554	2.847816
CESC	SBS21	Mismatchrepair	189	44	6	29	0.866972	0.88	0.12	0.133028	0.967461	0.410005	2.28285
CESC	SBS22	Aristolochic acid	184	46	4	34	0.844037	0.92	0.08	0.155963	0.54249	0.193988	1.51708
CESC	SBS23	Unknown	197	45	5	21	0.90367	0.9	0.1	0.09633	1.153646	0.45374	2.933176
CESC	SBS24	Aflatoxin	196	41	9	22	0.899083	0.82	0.18	0.100917	1.565932	0.756319	3.242207
CESC	SBS25	Chemotherapy	211	48	2	7	0.96789	0.96	0.04	0.03211	1.524658	0.363735	6.390874
CESC	SBS26	Mismatchrepair	173	36	14	45	0.793578	0.72	0.28	0.206422	1.39325	0.748285	2.594126
CESC	SBS28	Unknown	204	47	3	14	0.93578	0.94	0.06	0.06422	1.418833	0.426619	4.718695
CESC	SBS29	Tobacco chewing in Hollst	192	47	3	26	0.880734	0.94	0.06	0.119266	0.563979	0.173992	1.828092
CESC	SBS20	Mismatchrepair + POLD1mut	189	40	10	29	0.866972	0.8	0.2	0.133028	1.426297	0.695394	2.925423
CESC	SBS30	BER repair-NTHL1mut	177	37	13	41	0.811927	0.74	0.26	0.188073	1.381189	0.732719	2.603566
CESC	SBS31	PLChemotherapy	168	41	9	50	0.770642	0.82	0.18	0.229358	0.7782	0.375931	1.610924
CESC	SBS32	AZA Chemotherapy	193	46	4	25	0.885321	0.92	0.08	0.114679	0.715853	0.256868	1.994974
CESC	SBS33	Unknown	124	35	15	94	0.568807	0.7	0.3	0.431193	0.589348	0.320948	1.082206
CESC	SBS34	Unknown	180	34	16	38	0.825688	0.68	0.32	0.174312	2.482626	1.352687	4.556438
CESC	SBS35	PLChemotherapy	201	42	8	17	0.922018	0.84	0.16	0.077982	1.884224	0.875035	4.05732
CESC	SBS36	BERrepair MUTY	194	46	4	24	0.889908	0.92	0.08	0.110092	0.607591	0.217995	1.693461
CESC	SBS37	Unknown	205	44	6	13	0.940367	0.88	0.12	0.059633	2.509865	1.036654	6.076687
CESC	SBS38	UV	169	32	18	49	0.775229	0.64	0.36	0.224771	1.905985	1.062727	3.418356
CESC	SBS39	Unknown	69	19	31	149	0.316514	0.38	0.62	0.683486	0.590844	0.330015	1.057821
CESC	SBS39	Unknown	69	19	31	149	0.316514	0.38	0.62	0.683486	0.590844	0.330015	1.057821
CESC	SBS42	Haloalkane	212	46	4	6	0.972477	0.92	0.08	0.027523	2.066647	0.73589	5.803897
CESC	SBS84	Actind cytidinedeaminase	196	45	5	22	0.899083	0.9	0.1	0.100917	0.93845	0.367073	2.399217
CESC	SBS85	Actind cytidinedeaminase	200	46	4	18	0.917431	0.92	0.08	0.082569	1.128717	0.401412	3.173797
CESC	SBS3	Homologous repair
CESC	SBS40	Unknown
CESC	SBS41	Unknown
CESC	SBS44	Mismatchrepair
CESC	SBS9	PolETA Somatichypermutation
COAD	SBS1	Endogenous clock-like age	158	36	20	148	0.51634	0.642857	0.357143	0.48366	0.683255	0.385238	1.211815
COAD	SBS2	Endogenous Apobec3a	272	46	10	34	0.888889	0.821429	0.178571	0.111111	1.53501	0.757508	3.110536
COAD	SBS4	Tobacco	236	50	6	70	0.771242	0.892857	0.107143	0.228758	0.42192	0.179614	0.991107
COAD	SBS6	Mismatchrepair	210	43	13	96	0.686275	0.767857	0.232143	0.313725	0.918573	0.488485	1.727332
COAD	SBS7a	UV	269	52	4	37	0.879085	0.928571	0.071429	0.120915	0.521596	0.18786	1.448217
COAD	SBS7b	UV	294	56	0	12	0.960784	1	0	0.039216	8.92E−07	0
COAD	SBS7c	UV	267	55	1	39	0.872549	0.982143	0.017857	0.127451	0.13014	0.017965	0.94273
COAD	SBS7d	UV	235	38	18	71	0.767974	0.678571	0.321429	0.232026	1.181115	0.668342	2.087306
COAD	SBS8	Unknown	275	49	7	31	0.898693	0.875	0.125	0.101307	1.458696	0.655088	3.248103
COAD	SBS10a	Polymerase epsilon hyperm	269	46	10	37	0.879085	0.821429	0.178571	0.120915	2.417657	1.187557	4.921923
COAD	SBS10b	Polymerase epsilon mutati	221	34	22	85	0.722222	0.607143	0.392857	0.277778	1.772984	1.030194	3.051339
COAD	SBS11	Temozolo Chemotherapy	288	52	4	18	0.941176	0.928571	0.071429	0.058824	1.588154	0.548924	4.594866
COAD	SBS12	Liver cancer	244	49	7	62	0.797386	0.875	0.125	0.202614	0.811695	0.361912	1.820468
COAD	SBS13	Endogenous apobec	155	33	23	151	0.506536	0.589286	0.410714	0.493464	0.7579	0.443277	1.295829
COAD	SBS14	Mismatchrepair + PolEpsil	253	49	7	53	0.826797	0.875	0.125	0.173203	0.962922	0.430681	2.152917
COAD	SBS15	Mismatchrepair	260	49	7	46	0.849673	0.875	0.125	0.150327	1.198488	0.529964	2.710323
COAD	SBS16	Unknown	241	48	8	65	0.787582	0.857143	0.142857	0.212418	0.830431	0.389705	1.769584
COAD	SBS17a	Unknown	145	19	37	161	0.473856	0.339286	0.660714	0.526144	1.537468	0.878091	2.691984
COAD	SBS17b	Unknown	277	45	11	29	0.905229	0.803571	0.196429	0.094771	3.124651	1.567689	6.227922
COAD	SBS18	ReactiveOxy	271	45	11	35	0.885621	0.803571	0.196429	0.114379	1.838655	0.946737	3.570846
COAD	SBS19	Unknown	275	49	7	31	0.898693	0.875	0.125	0.101307	1.383912	0.622125	3.078505
COAD	SBS21	Mismatchrepair	274	46	10	32	0.895425	0.821429	0.178571	0.104575	2.401711	1.191516	4.841074
COAD	SBS22	Aristolochic acid	279	45	11	27	0.911765	0.803571	0.196429	0.088235	1.815568	0.908773	3.627184
COAD	SBS23	Unknown	283	50	6	23	0.924837	0.892857	0.107143	0.075163	1.156822	0.494046	2.708728
COAD	SBS24	Aflatoxin	239	46	10	67	0.781046	0.821429	0.178571	0.218954	0.796819	0.396088	1.602976
COAD	SBS25	Chemotherapy	289	44	12	17	0.944444	0.785714	0.214286	0.055556	4.379459	2.261667	8.480319
COAD	SBS26	Mismatchrepair	210	27	29	96	0.686275	0.482143	0.517857	0.313725	2.832078	1.663024	4.822939
COAD	SBS28	Unknown	264	47	9	42	0.862745	0.839286	0.160714	0.137255	0.913583	0.441247	1.891536
COAD	SBS29	Tobacco chewing in Hollst	259	52	4	47	0.846405	0.928571	0.071429	0.153595	0.370419	0.130157	1.054189
COAD	SBS20	Mismatchrepair + POLD1mut	235	46	10	71	0.767974	0.821429	0.178571	0.232026	1.024278	0.509805	2.057933
COAD	SBS30	BER repair-NTHL1mut	270	42	14	36	0.882353	0.75	0.25	0.117647	2.065213	1.118217	3.8142
COAD	SBS31	PLChemotherapy	250	49	7	56	0.816993	0.875	0.125	0.183007	0.75238	0.338561	1.672006
COAD	SBS32	AZA Chemotherapy	258	50	6	48	0.843137	0.892857	0.107143	0.156863	0.638759	0.272242	1.498716
COAD	SBS33	Unknown	218	35	21	88	0.712418	0.625	0.375	0.287582	2.005136	1.157394	3.473815
COAD	SBS34	Unknown	239	46	10	67	0.781046	0.821429	0.178571	0.218954	0.882891	0.442378	1.762057
COAD	SBS35	PLChemotherapy	241	46	10	65	0.787582	0.821429	0.178571	0.212418	0.916887	0.459244	1.830578
COAD	SBS36	BERrepair MUTY	270	48	8	36	0.882353	0.857143	0.142857	0.117647	1.082904	0.502646	2.333018
COAD	SBS37	Unknown	276	48	8	30	0.901961	0.857143	0.142857	0.098039	1.572165	0.731335	3.379712
COAD	SBS38	UV	260	43	13	46	0.849673	0.767857	0.232143	0.150327	1.392243	0.745083	2.601511
COAD	SBS39	Unknown	275	44	12	31	0.898693	0.785714	0.214286	0.101307	1.888321	0.981806	3.631835
COAD	SBS42	Haloalkane	287	49	7	19	0.937908	0.875	0.125	0.062092	2.219681	0.97549	5.05078
COAD	SBS84	Actind cytidinedeaminase	278	50	6	28	0.908497	0.892857	0.107143	0.091503	1.057629	0.449534	2.488307
COAD	SBS85	Actind cytidinedeaminase	282	53	3	24	0.921569	0.946429	0.053571	0.078431	0.666061	0.206213	2.151354
COAD	SBS3	Homologous repair
COAD	SBS40	Unknown
COAD	SBS41	Unknown
COAD	SBS44	Mismatchrepair
COAD	SBS9	PolETA Somatichypermutation
HNSC	SBS1	Endogenous clock-like age	69	35	94	281	0.197143	0.271318	0.728682	0.802857	0.724196	0.487196	1.076486
HNSC	SBS2	Endogenous Apobec3a	89	20	109	261	0.254286	0.155039	0.844961	0.745714	1.463775	0.902592	2.373871
HNSC	SBS4	Tobacco	304	115	14	46	0.868571	0.891473	0.108527	0.131429	0.730471	0.416722	1.280441
HNSC	SBS6	Mismatchrepair	234	89	40	116	0.668571	0.689922	0.310078	0.331429	0.80349	0.550644	1.172439
HNSC	SBS7a	UV	187	61	68	163	0.534286	0.472868	0.527132	0.465714	1.3379	0.943421	1.897325
HNSC	SBS7a	UV	187	61	68	163	0.534286	0.472868	0.527132	0.465714	1.3379	0.943421	1.897325
HNSC	SBS7b	UV	227	88	41	123	0.648571	0.682171	0.317829	0.351429	0.728851	0.500165	1.062097
HNSC	SBS7c	UV	300	99	30	50	0.857143	0.767442	0.232558	0.142857	1.519512	1.003616	2.300596
HNSC	SBS7d	UV	269	95	34	81	0.768571	0.736434	0.263566	0.231429	1.162953	0.783371	1.726461
HNSC	SBS8	Unknown	311	109	20	39	0.888571	0.844961	0.155039	0.111429	1.411243	0.874135	2.278374
HNSC	SBS10a	Polymerase epsilon hyperm	316	114	15	34	0.902857	0.883721	0.116279	0.097143	1.312249	0.762574	2.258138
HNSC	SBS10b	Polymerase epsilon mutati	75	39	90	275	0.214286	0.302326	0.697674	0.785714	0.694424	0.473708	1.01798
HNSC	SBS11	Temozolo Chemotherapy	309	121	8	41	0.882857	0.937984	0.062016	0.117143	0.592884	0.289324	1.214942
HNSC	SBS12	Liver cancer	313	117	12	37	0.894286	0.906977	0.093023	0.105714	0.823754	0.453156	1.497434
HNSC	SBS13	Endogenous apobec	143	37	92	207	0.408571	0.286822	0.713178	0.591429	1.233165	0.830552	1.830947
HNSC	SBS14	Mismatchrepair + PolEpsil	317	113	16	33	0.905714	0.875969	0.124031	0.094286	1.090116	0.630925	1.883508
HNSC	SBS15	Mismatchrepair	239	96	33	111	0.682857	0.744186	0.255814	0.317143	0.726038	0.487862	1.080492
HNSC	SBS16	Unknown	238	74	55	112	0.68	0.573643	0.426357	0.32	1.489074	1.043252	2.125413
HNSC	SBS17a	Unknown	313	110	19	37	0.894286	0.852713	0.147287	0.105714	1.232297	0.754167	2.013552
HNSC	SBS17b	Unknown	285	104	25	65	0.814286	0.806202	0.193798	0.185714	0.880317	0.563962	1.374133
HNSC	SBS18	ReactiveOxy	278	111	18	72	0.794286	0.860465	0.139535	0.205714	0.711059	0.427079	1.183868
HNSC	SBS19	Unknown	242	99	30	108	0.691429	0.767442	0.232558	0.308571	0.688823	0.456755	1.0388
HNSC	SBS21	Mismatchrepair	291	99	30	59	0.831429	0.767442	0.232558	0.168571	1.303049	0.859598	1.975267
HNSC	SBS22	Aristolochic acid	194	83	46	156	0.554286	0.643411	0.356589	0.445714	0.681967	0.473663	0.981877
HNSC	SBS23	Unknown	309	109	20	41	0.882857	0.844961	0.155039	0.117143	1.354365	0.837198	2.191006
HNSC	SBS24	Aflatoxin	244	77	52	106	0.697143	0.596899	0.403101	0.302857	1.290572	0.904553	1.841326
HNSC	SBS25	Chemotherapy	316	107	22	34	0.902857	0.829457	0.170543	0.097143	1.477547	0.927779	2.353088
HNSC	SBS26	Mismatchrepair	240	80	49	110	0.685714	0.620155	0.379845	0.314286	1.218511	0.851351	1.744015
HNSC	SBS28	Unknown	310	119	10	40	0.885714	0.922481	0.077519	0.114286	0.877571	0.456841	1.685776
HNSC	SBS29	Tobacco chewing in Hollst	302	96	33	48	0.862857	0.744186	0.255814	0.137143	1.579499	1.058431	2.357091
HNSC	SBS20	Mismatchrepair + POLD1mut	295	117	12	55	0.842857	0.906977	0.093023	0.157143	0.630618	0.347427	1.144638
HNSC	SBS30	BER repair-NTHL1mut	261	88	41	89	0.745714	0.682171	0.317829	0.254286	1.146513	0.788941	1.666148
HNSC	SBS31	PLChemotherapy	318	107	22	32	0.908571	0.829457	0.170543	0.091429	1.606574	1.005138	2.567886
HNSC	SBS32	AZA Chemotherapy	318	112	17	32	0.908571	0.868217	0.131783	0.091429	1.276771	0.764324	2.13279
HNSC	SBS33	Unknown	299	103	26	51	0.854286	0.79845	0.20155	0.145714	1.181745	0.763197	1.829833
HNSC	SBS34	Unknown	312	110	19	38	0.891429	0.852713	0.147287	0.108571	1.515788	0.919947	2.497552
HNSC	SBS35	PLChemotherapy	310	106	23	40	0.885714	0.821705	0.178295	0.114286	1.663212	1.050589	2.63307
HNSC	SBS36	BERrepair MUTY	319	111	18	31	0.911429	0.860465	0.139535	0.088571	1.659203	1.000755	2.750876
HNSC	SBS38	UV	308	105	24	42	0.88	0.813953	0.186047	0.12	1.34324	0.859231	2.099894
HNSC	SBS39	Unknown	280	98	31	70	0.8	0.75969	0.24031	0.2	1.120706	0.746561	1.682359
HNSC	SBS42	Haloalkane	311	114	15	39	0.888571	0.883721	0.116279	0.111429	1.232683	0.716849	2.119706
HNSC	SBS84	Actind cytidinedeaminase	319	112	17	31	0.911429	0.868217	0.131783	0.088571	1.651075	0.973713	2.799643
HNSC	SBS3	Homologous repair
HNSC	SBS37	Unknown
HNSC	SBS40	Unknown
HNSC	SBS41	Unknown
HNSC	SBS44	Mismatchrepair
HNSC	SBS85	Actind cytidinedeaminase
HNSC	SBS9	PolETA Somatichypermutation
LGG	SBS1	Endogenous clock-like age	337	76	35	39	0.896277	0.684685	0.315315	0.103723	3.654361	2.226141	5.998882
LGG	SBS2	Endogenous Apobec3a	298	82	29	78	0.792553	0.738739	0.261261	0.207447	0.934106	0.599564	1.455313
LGG	SBS4	Tobacco	343	95	16	33	0.912234	0.855856	0.144144	0.087766	1.575856	0.915882	2.711397
LGG	SBS6	Mismatchrepair	340	93	18	36	0.904255	0.837838	0.162162	0.095745	1.180319	0.701016	1.987333
LGG	SBS7a	UV	326	92	19	50	0.867021	0.828829	0.171171	0.132979	1.22653	0.737834	2.038908
LGG	SBS7b	UV	259	82	29	117	0.68883	0.738739	0.261261	0.31117	0.780855	0.506413	1.204025
LGG	SBS7c	UV	333	100	11	43	0.885638	0.900901	0.099099	0.114362	0.699547	0.371036	1.318918
LGG	SBS7d	UV	309	90	21	67	0.821809	0.810811	0.189189	0.178191	0.967204	0.596647	1.567901
LGG	SBS8	Unknown	338	89	22	38	0.898936	0.801802	0.198198	0.101064	2.25033	1.395927	3.627687
LGG	SBS10a	Polymerase epsilon hyperm	311	87	24	65	0.827128	0.783784	0.216216	0.172872	0.910572	0.569912	1.454857
LGG	SBS10b	Polymerase epsilon mutati	331	90	21	45	0.880319	0.810811	0.189189	0.119681	1.600953	0.978485	2.619406
LGG	SBS11	Temozolo Chemotherapy	340	93	18	36	0.904255	0.837838	0.162162	0.095745	1.267021	0.757543	2.119143
LGG	SBS12	Liver cancer	324	103	8	52	0.861702	0.927928	0.072072	0.138298	0.302621	0.144395	0.634227
LGG	SBS13	Endogenous apobec	210	60	51	166	0.558511	0.540541	0.459459	0.441489	1.29013	0.876994	1.897889
LGG	SBS14	Mismatchrepair + PolEpsil	333	101	10	43	0.885638	0.90991	0.09009	0.114362	1.040545	0.539013	2.008735
LGG	SBS15	Mismatchrepair	326	93	18	50	0.867021	0.837838	0.162162	0.132979	1.089912	0.637901	1.862214
LGG	SBS16	Unknown	261	79	32	115	0.694149	0.711712	0.288288	0.305851	0.683213	0.444678	1.049703
LGG	SBS17a	Unknown	324	96	15	52	0.861702	0.864865	0.135135	0.138298	1.385515	0.7889	2.433325
LGG	SBS17b	Unknown	339	93	18	37	0.901596	0.837838	0.162162	0.098404	1.143015	0.675108	1.93522
LGG	SBS18	ReactiveOxy	371	109	2	5	0.986702	0.981982	0.018018	0.013298	2.386319	0.574945	9.904458
LGG	SBS19	Unknown	345	92	19	31	0.917553	0.828829	0.171171	0.082447	0.935787	0.551879	1.586755
LGG	SBS21	Mismatchrepair	339	98	13	37	0.901596	0.882883	0.117117	0.098404	0.533238	0.291483	0.975503
LGG	SBS22	Aristolochic acid	342	95	16	34	0.909574	0.855856	0.144144	0.090426	1.194701	0.680095	2.098691
LGG	SBS23	Unknown	296	91	20	80	0.787234	0.81982	0.18018	0.212766	0.603005	0.364159	0.998507
LGG	SBS24	Aflatoxin	318	90	21	58	0.845745	0.810811	0.189189	0.154255	1.136254	0.696567	1.853482
LGG	SBS25	Chemotherapy	370	106	5	6	0.984043	0.954955	0.045045	0.015957	7.7913	3.043813	19.94352
LGG	SBS26	Mismatchrepair	264	87	24	112	0.702128	0.783784	0.216216	0.297872	0.792357	0.49663	1.264179
LGG	SBS28	Unknown	338	95	16	38	0.898936	0.855856	0.144144	0.101064	1.140422	0.66374	1.959446
LGG	SBS29	Tobacco chewing in Hollst	321	91	20	55	0.853723	0.81982	0.18018	0.146277	1.220996	0.746381	1.997413
LGG	SBS20	Mismatchrepair + POLD1mut	338	99	12	38	0.898936	0.891892	0.108108	0.101064	1.371327	0.739201	2.544014
LGG	SBS30	BER repair-NTHL1mut	338	96	15	38	0.898936	0.864865	0.135135	0.101064	1.743756	0.98859	3.075781
LGG	SBS31	PLChemotherapy	320	86	25	56	0.851064	0.774775	0.225225	0.148936	1.697361	1.066546	2.701276
LGG	SBS32	AZA Chemotherapy	337	96	15	39	0.896277	0.864865	0.135135	0.103723	1.268465	0.723936	2.222575
LGG	SBS33	Unknown	342	94	17	34	0.909574	0.846847	0.153153	0.090426	1.690807	0.998442	2.863289
LGG	SBS34	Unknown	329	100	11	47	0.875	0.900901	0.099099	0.125	1.094364	0.57817	2.071421
LGG	SBS35	PLChemotherapy	323	101	10	53	0.859043	0.90991	0.09009	0.140957	0.93842	0.481539	1.828785
LGG	SBS36	BERrepair MUTY	368	108	3	8	0.978723	0.972973	0.027027	0.021277	1.016654	0.320422	3.225703
LGG	SBS37	Unknown	304	93	18	72	0.808511	0.837838	0.162162	0.191489	0.990987	0.589704	1.665334
LGG	SBS38	UV	336	98	13	40	0.893617	0.882883	0.117117	0.106383	0.870465	0.485337	1.561202
LGG	SBS39	Unknown	269	66	45	107	0.715426	0.594595	0.405405	0.284574	1.260789	0.852748	1.864078
LGG	SBS42	Haloalkane	308	95	16	68	0.819149	0.855856	0.144144	0.180851	0.704425	0.403211	1.230657
LGG	SBS84	Actind cytidinedeaminase	306	93	18	70	0.81383	0.837838	0.162162	0.18617	0.869971	0.516372	1.465707
LGG	SBS85	Actind cytidinedeaminase	321	104	7	55	0.853723	0.936937	0.063063	0.146277	0.727195	0.333993	1.583307
LGG	SBS3	Homologous repair
LGG	SBS40	Unknown
LGG	SBS41	Unknown
LGG	SBS44	Mismatchrepair
LGG	SBS9	PolETA Somatichypermutation
LIHC	SBS1	Endogenous clock-like age	142	24	51	127	0.527881	0.32	0.68	0.472119	2.307518	1.400122	3.802983
LIHC	SBS2	Endogenous Apobec3a	228	60	15	41	0.847584	0.8	0.2	0.152416	1.410724	0.783835	2.538982
LIHC	SBS3	Homologous repair	232	67	8	37	0.862454	0.893333	0.106667	0.137546	0.792611	0.367915	1.707551
LIHC	SBS4	Tobacco	207	51	24	62	0.769517	0.68	0.32	0.230483	2.039176	1.22491	3.394732
LIHC	SBS6	Mismatchrepair	117	46	29	152	0.434944	0.613333	0.386667	0.565056	0.516619	0.317067	0.841764
LIHC	SBS7a	UV	230	59	16	39	0.855019	0.786667	0.213333	0.144981	2.177722	1.228743	3.859613
LIHC	SBS7b	UV	230	66	9	39	0.855019	0.88	0.12	0.144981	0.704507	0.342765	1.448018
LIHC	SBS7d	UV	216	61	14	53	0.802974	0.813333	0.186667	0.197026	0.870813	0.47848	1.584845
LIHC	SBS8	Unknown	228	65	10	41	0.847584	0.866667	0.133333	0.152416	0.75899	0.378647	1.521379
LIHC	SBS10a	Polymerase epsilon hyperm	164	56	19	105	0.609665	0.746667	0.253333	0.390335	0.669012	0.396031	1.130158
LIHC	SBS10b	Polymerase epsilon mutati	169	48	27	100	0.628253	0.64	0.36	0.371747	0.92262	0.570552	1.491937
LIHC	SBS11	Temozolo Chemotherapy	239	67	8	30	0.888476	0.893333	0.106667	0.111524	1.413619	0.668811	2.987868
LIHC	SBS12	Liver cancer	243	64	11	26	0.903346	0.853333	0.146667	0.096654	1.64297	0.852176	3.167594
LIHC	SBS13	Endogenous apobec	244	63	12	25	0.907063	0.84	0.16	0.092937	1.064942	0.5535	2.048964
LIHC	SBS14	Mismatchrepair + PolEpsil	241	65	10	28	0.895911	0.866667	0.133333	0.104089	1.338222	0.678796	2.638257
LIHC	SBS15	Mismatchrepair	225	60	15	44	0.836431	0.8	0.2	0.163569	1.689097	0.943703	3.023246
LIHC	SBS16	Unknown	120	45	30	149	0.446097	0.6	0.4	0.553903	0.701739	0.433954	1.13477
LIHC	SBS17a	Unknown	127	29	46	142	0.472119	0.386667	0.613333	0.527881	1.371471	0.84631	2.22251
LIHC	SBS17b	Unknown	242	66	9	27	0.899628	0.88	0.12	0.100372	1.755056	0.847447	3.63471
LIHC	SBS18	ReactiveOxy	244	63	12	25	0.907063	0.84	0.16	0.092937	1.220194	0.642692	2.316618
LIHC	SBS19	Unknown	232	55	20	37	0.862454	0.733333	0.266667	0.137546	2.019911	1.174668	3.473357
LIHC	SBS21	Mismatchrepair	228	55	20	41	0.847584	0.733333	0.266667	0.152416	1.896919	1.115125	3.226814
LIHC	SBS22	Aristolochic acid	185	63	12	84	0.687732	0.84	0.16	0.312268	0.635987	0.338277	1.195705
LIHC	SBS23	Unknown	242	65	10	27	0.899628	0.866667	0.133333	0.100372	1.547397	0.777011	3.081602
LIHC	SBS24	Aflatoxin	247	61	14	22	0.918216	0.813333	0.186667	0.081784	3.583024	1.907359	6.730806
LIHC	SBS25	Chemotherapy	222	59	16	47	0.825279	0.786667	0.213333	0.174721	1.221011	0.671867	2.21899
LIHC	SBS26	Mismatchrepair	162	37	38	107	0.60223	0.493333	0.506667	0.39777	1.575241	0.999346	2.483007
LIHC	SBS28	Unknown	174	53	22	95	0.64684	0.706667	0.293333	0.35316	0.691459	0.41394	1.155039
LIHC	SBS29	Tobacco chewing in Hollst	232	69	6	37	0.862454	0.92	0.08	0.137546	0.690768	0.297299	1.604983
LIHC	SBS20	Mismatchrepair + POLD1mut	225	61	14	44	0.836431	0.813333	0.186667	0.163569	1.598865	0.88096	2.901799
LIHC	SBS30	BER repair-NTHL1mut	210	57	18	59	0.780669	0.76	0.24	0.219331	0.995287	0.574617	1.723924
LIHC	SBS31	PLChemotherapy	201	59	16	68	0.747212	0.786667	0.213333	0.252788	1.020253	0.580073	1.794457
LIHC	SBS32	AZA Chemotherapy	221	69	6	48	0.821561	0.92	0.08	0.178439	0.446234	0.191015	1.042456
LIHC	SBS33	Unknown	232	69	6	37	0.862454	0.92	0.08	0.137546	0.605685	0.258415	1.419635
LIHC	SBS34	Unknown	209	48	27	60	0.776952	0.64	0.36	0.223048	1.424505	0.882181	2.300227
LIHC	SBS35	PLChemotherapy	237	66	9	32	0.881041	0.88	0.12	0.118959	1.930625	0.937713	3.974898
LIHC	SBS36	BERrepair MUTY	233	65	10	36	0.866171	0.866667	0.133333	0.133829	0.890112	0.438055	1.808676
LIHC	SBS37	Unknown	231	66	9	38	0.858736	0.88	0.12	0.141264	0.737196	0.361768	1.502227
LIHC	SBS38	UV	243	61	14	26	0.903346	0.813333	0.186667	0.096654	1.514717	0.831834	2.758204
LIHC	SBS39	Unknown	118	20	55	151	0.438662	0.266667	0.733333	0.561338	2.02942	1.197005	3.440708
LIHC	SBS42	Haloalkane	219	65	10	50	0.814126	0.866667	0.133333	0.185874	0.699331	0.353403	1.38387
LIHC	SBS85	Actind cytidinedeaminase	258	70	5	11	0.959108	0.933333	0.066667	0.040892	1.653323	0.644525	4.241073
LIHC	SBS40	Unknown
LIHC	SBS41	Unknown
LIHC	SBS44	Mismatchrepair
LIHC	SBS7c	UV
LIHC	SBS84	Actind cytidinedeaminase
LIHC	SBS9	PolETA Somatichypermutati
LUAD	SBS1	Endogenous clock-like age	31	14	94	314	0.089855	0.12963	0.87037	0.910145	0.733877	0.417822	1.289009
LUAD	SBS2	Endogenous Apobec3a	209	59	49	136	0.605797	0.546296	0.453704	0.394203	1.188411	0.809585	1.744499
LUAD	SBS3	Homologous repair	334	105	3	11	0.968116	0.972222	0.027778	0.031884	1.335772	0.419647	4.251875
LUAD	SBS4	Tobacco	244	84	24	101	0.707246	0.777778	0.222222	0.292754	0.573131	0.356218	0.92213
LUAD	SBS6	Mismatchrepair	310	92	16	35	0.898551	0.851852	0.148148	0.101449	1.715056	1.004803	2.927357
LUAD	SBS7a	UV	269	76	32	76	0.77971	0.703704	0.296296	0.22029	1.296047	0.853312	1.968492
LUAD	SBS7b	UV	265	86	22	80	0.768116	0.796296	0.203704	0.231884	0.812684	0.504455	1.309244
LUAD	SBS7c	UV	302	103	5	43	0.875362	0.953704	0.046296	0.124638	0.343792	0.138734	0.851939
LUAD	SBS7d	UV	269	89	19	76	0.77971	0.824074	0.175926	0.22029	0.633052	0.384388	1.042579
LUAD	SBS8	Unknown	327	104	4	18	0.947826	0.962963	0.037037	0.052174	0.897159	0.328945	2.446899
LUAD	SBS10a	Polymerase epsilon hyperm	279	94	14	66	0.808696	0.87037	0.12963	0.191304	0.630735	0.358087	1.110975
LUAD	SBS10b	Polymerase epsilon mutati	168	39	69	177	0.486957	0.361111	0.638889	0.513043	1.529222	1.026595	2.277939
LUAD	SBS11	Temozolo Chemotherapy	327	101	7	18	0.947826	0.935185	0.064815	0.052174	1.185867	0.544163	2.584298
LUAD	SBS12	Liver cancer	314	89	19	31	0.910145	0.824074	0.175926	0.089855	1.493464	0.90645	2.460626
LUAD	SBS13	Endogenous apobec	254	73	35	91	0.736232	0.675926	0.324074	0.263768	1.290129	0.860019	1.935345
LUAD	SBS14	Mismatchrepair + PolEpsil	301	92	16	44	0.872464	0.851852	0.148148	0.127536	0.886569	0.517276	1.519509
LUAD	SBS15	Mismatchrepair	274	97	11	71	0.794203	0.898148	0.101852	0.205797	0.533988	0.285237	0.999671
LUAD	SBS16	Unknown	305	94	14	40	0.884058	0.87037	0.12963	0.115942	0.768642	0.4343	1.360374
LUAD	SBS17a	Unknown	294	94	14	51	0.852174	0.87037	0.12963	0.147826	0.765501	0.433921	1.350457
LUAD	SBS17b	Unknown	256	66	42	89	0.742029	0.611111	0.388889	0.257971	1.638175	1.10399	2.430836
LUAD	SBS18	ReactiveOxy	303	92	16	42	0.878261	0.851852	0.148148	0.121739	0.983549	0.572817	1.688791
LUAD	SBS19	Unknown	293	85	23	52	0.849275	0.787037	0.212963	0.150725	1.418974	0.888507	2.266147
LUAD	SBS21	Mismatchrepair	205	79	29	140	0.594203	0.731481	0.268519	0.405797	0.698761	0.452481	1.079087
LUAD	SBS22	Aristolochic acid	296	86	22	49	0.857971	0.796296	0.203704	0.142029	1.131754	0.70334	1.821121
LUAD	SBS23	Unknown	311	94	14	34	0.901449	0.87037	0.12963	0.098551	1.390561	0.788633	2.451914
LUAD	SBS24	Aflatoxin	184	68	40	161	0.533333	0.62963	0.37037	0.466667	0.635345	0.422881	0.954554
LUAD	SBS25	Chemotherapy	308	84	24	37	0.892754	0.777778	0.222222	0.107246	1.824833	1.147991	2.900734
LUAD	SBS26	Mismatchrepair	272	83	25	73	0.788406	0.768519	0.231481	0.211594	1.394711	0.887527	2.191729
LUAD	SBS28	Unknown	311	92	16	34	0.901449	0.851852	0.148148	0.098551	1.495207	0.867465	2.577213
LUAD	SBS29	Tobacco chewing in Hollst	298	85	23	47	0.863768	0.787037	0.212963	0.136232	1.65353	1.02876	2.657726
LUAD	SBS20	Mismatchrepair + POLD1mut	274	92	16	71	0.794203	0.851852	0.148148	0.205797	0.785162	0.458368	1.344943
LUAD	SBS30	BER repair-NTHL1mut	312	93	15	33	0.904348	0.861111	0.138889	0.095652	1.409251	0.791041	2.510601
LUAD	SBS31	PLChemotherapy	297	103	5	48	0.86087	0.953704	0.046296	0.13913	0.303261	0.123098	0.747107
LUAD	SBS32	AZA Chemotherapy	290	92	16	55	0.84058	0.851852	0.148148	0.15942	0.878322	0.515459	1.496625
LUAD	SBS33	Unknown	305	89	19	40	0.884058	0.824074	0.175926	0.115942	1.544252	0.934514	2.551823
LUAD	SBS34	Unknown	302	95	13	43	0.875362	0.87963	0.12037	0.124638	0.877711	0.490283	1.571288
LUAD	SBS35	PLChemotherapy	302	93	15	43	0.875362	0.861111	0.138889	0.124638	1.095492	0.628278	1.910147
LUAD	SBS36	BERrepair MUTY	299	96	12	46	0.866667	0.888889	0.111111	0.133333	0.913264	0.499491	1.669803
LUAD	SBS37	Unknown	328	103	5	17	0.950725	0.953704	0.046296	0.049275	1.069958	0.432459	2.647211
LUAD	SBS38	UV	286	94	14	59	0.828986	0.87037	0.12963	0.171014	0.934917	0.528888	1.652654
LUAD	SBS39	Unknown	221	58	50	124	0.64058	0.537037	0.462963	0.35942	1.344978	0.909636	1.988671
LUAD	SBS42	Haloalkane	290	85	23	55	0.84058	0.787037	0.212963	0.15942	1.524832	0.95564	2.433042
LUAD	SBS84	Actind cytidinedeaminase	326	99	9	19	0.944928	0.916667	0.083333	0.055072	1.48422	0.739439	2.97916
LUAD	SBS40	Unknown
LUAD	SBS41	Unknown
LUAD	SBS44	Mismatchrepair
LUAD	SBS85	Actind cytidinedeaminase
LUAD	SBS9	PolETA Somatichypermutation
LUSC	SBS1	Endogenous clock-like age	34	7	80	298	0.10241	0.08046	0.91954	0.89759	1.279408	0.588499	2.781455
LUSC	SBS2	Endogenous Apobec3a	171	49	38	161	0.51506	0.563218	0.436782	0.48494	0.79799	0.519958	1.22469
LUSC	SBS3	Homologous repair	308	85	2	24	0.927711	0.977011	0.022989	0.072289	0.448456	0.109569	1.83549
LUSC	SBS4	Tobacco	67	25	62	265	0.201807	0.287356	0.712644	0.798193	0.694503	0.435822	1.106721
LUSC	SBS6	Mismatchrepair	155	49	38	177	0.466867	0.563218	0.436782	0.533133	0.678035	0.441494	1.041309
LUSC	SBS7a	UV	275	73	14	57	0.828313	0.83908	0.16092	0.171687	0.792916	0.44546	1.411386
LUSC	SBS7b	UV	268	75	12	64	0.807229	0.862069	0.137931	0.192771	0.44868	0.242118	0.831471
LUSC	SBS7c	UV	291	75	12	41	0.876506	0.862069	0.137931	0.123494	0.963857	0.520855	1.783644
LUSC	SBS7d	UV	264	71	16	68	0.795181	0.816092	0.183908	0.204819	0.772996	0.445741	1.340516
LUSC	SBS8	Unknown	292	78	9	40	0.879518	0.896552	0.103448	0.120482	0.657873	0.323748	1.336831
LUSC	SBS10a	Polymerase epsilon hyperm	279	78	9	53	0.840361	0.896552	0.103448	0.159639	0.490029	0.244788	0.980966
LUSC	SBS10b	Polymerase epsilon mutati	269	73	14	63	0.810241	0.83908	0.16092	0.189759	0.833354	0.463902	1.497038
LUSC	SBS11	Temozolo Chemotherapy	308	77	10	24	0.927711	0.885057	0.114943	0.072289	1.173913	0.605772	2.274901
LUSC	SBS12	Liver cancer	254	65	22	78	0.76506	0.747126	0.252874	0.23494	1.09692	0.670809	1.793707
LUSC	SBS13	Endogenous apobec	283	77	10	49	0.85241	0.885057	0.114943	0.14759	0.730095	0.373204	1.428276
LUSC	SBS14	Mismatchrepair + PolEpsil	294	82	5	38	0.885542	0.942529	0.057471	0.114458	0.474683	0.192233	1.172142
LUSC	SBS15	Mismatchrepair	244	68	19	88	0.73494	0.781609	0.218391	0.26506	0.833796	0.497481	1.397471
LUSC	SBS16	Unknown	225	65	22	107	0.677711	0.747126	0.252874	0.322289	0.679955	0.417193	1.108212
LUSC	SBS17a	Unknown	179	37	50	153	0.539157	0.425287	0.574713	0.460843	1.375722	0.885895	2.136384
LUSC	SBS17b	Unknown	218	61	26	114	0.656627	0.701149	0.298851	0.343373	0.756875	0.477026	1.200898
LUSC	SBS18	ReactiveOxy	300	73	14	32	0.903614	0.83908	0.16092	0.096386	1.372819	0.761185	2.475918
LUSC	SBS19	Unknown	299	74	13	33	0.900602	0.850575	0.149425	0.099398	1.297718	0.715956	2.3522
LUSC	SBS21	Mismatchrepair	265	79	8	67	0.798193	0.908046	0.091954	0.201807	0.497314	0.239841	1.031191
LUSC	SBS22	Aristolochic acid	265	72	15	67	0.798193	0.827586	0.172414	0.201807	0.773138	0.435676	1.371989
LUSC	SBS23	Unknown	291	80	7	41	0.876506	0.91954	0.08046	0.123494	0.460011	0.208587	1.014492
LUSC	SBS24	Aflatoxin	65	26	61	267	0.195783	0.298851	0.701149	0.804217	0.505534	0.313239	0.815875
LUSC	SBS25	Chemotherapy	286	72	15	46	0.861446	0.827586	0.172414	0.138554	1.279828	0.720158	2.274445
LUSC	SBS26	Mismatchrepair	261	76	11	71	0.786145	0.873563	0.126437	0.213855	0.618706	0.325941	1.174435
LUSC	SBS28	Unknown	277	75	12	55	0.834337	0.862069	0.137931	0.165663	1.034856	0.557789	1.919949
LUSC	SBS29	Tobacco chewing in Hollst	259	58	29	73	0.78012	0.666667	0.333333	0.21988	1.335585	0.851907	2.093874
LUSC	SBS20	Mismatchrepair + POLD1mut	256	59	28	76	0.771084	0.678161	0.321839	0.228916	1.294239	0.821962	2.037874
LUSC	SBS30	BER repair-NTHL1mut	300	75	12	32	0.903614	0.862069	0.137931	0.096386	1.281303	0.690256	2.378447
LUSC	SBS31	PLChemotherapy	256	69	18	76	0.771084	0.793103	0.206897	0.228916	0.912378	0.541755	1.536549
LUSC	SBS32	AZA Chemotherapy	291	85	2	41	0.876506	0.977011	0.022989	0.123494	0.189726	0.046266	0.778019
LUSC	SBS33	Unknown	181	63	24	151	0.545181	0.724138	0.275862	0.454819	0.514801	0.320443	0.827044
LUSC	SBS34	Unknown	293	71	16	39	0.88253	0.816092	0.183908	0.11747	1.272937	0.73645	2.200243
LUSC	SBS35	PLChemotherapy	294	79	8	38	0.885542	0.908046	0.091954	0.114458	0.932935	0.44539	1.954172
LUSC	SBS36	BERrepair MUTY	289	80	7	43	0.870482	0.91954	0.08046	0.129518	0.429341	0.193442	0.952916
LUSC	SBS37	Unknown	320	82	5	12	0.963855	0.942529	0.057471	0.036145	1.709397	0.669463	4.364747
LUSC	SBS38	UV	274	63	24	58	0.825301	0.724138	0.275862	0.174699	1.457552	0.902748	2.353324
LUSC	SBS39	Unknown	49	16	71	283	0.14759	0.183908	0.816092	0.85241	0.529466	0.302905	0.925485
LUSC	SBS42	Haloalkane	294	79	8	38	0.885542	0.908046	0.091954	0.114458	0.84702	0.406289	1.765846
LUSC	SBS84	Actind cytidinedeaminase	306	80	7	26	0.921687	0.91954	0.08046	0.078313	0.93188	0.428123	2.028389
LUSC	SBS85	Actind cytidinedeaminase	320	84	3	12	0.963855	0.965517	0.034483	0.036145	1.841739	0.568644	5.965074
LUSC	SBS40	Unknown
LUSC	SBS41	Unknown
LUSC	SBS44	Mismatchrepair
LUSC	SBS9	PolETA Somatichypermutation
OV	SBS1	Endogenous clock-like age	114	98	69	58	0.662791	0.586826	0.413174	0.337209	1.489411	1.075751	2.062137
OV	SBS2	Endogenous Apobec3a	158	144	23	14	0.918605	0.862275	0.137725	0.081395	1.222058	0.784071	1.904708
OV	SBS3	Homologous repair	151	146	21	21	0.877907	0.874251	0.125749	0.122093	1.139907	0.719926	1.80489
OV	SBS4	Tobacco	107	116	51	65	0.622093	0.694611	0.305389	0.377907	0.793011	0.567107	1.108901
OV	SBS6	Mismatchrepair	140	133	34	32	0.813953	0.796407	0.203593	0.186047	0.769589	0.524927	1.128284
OV	SBS7a	UV	87	113	54	85	0.505814	0.676647	0.323353	0.494186	0.56687	0.407376	0.788809
OV	SBS7b	UV	117	122	45	55	0.680233	0.730539	0.269461	0.319767	0.785691	0.55564	1.110988
OV	SBS7c	UV	133	137	30	39	0.773256	0.820359	0.179641	0.226744	0.747078	0.500733	1.114617
OV	SBS7d	UV	142	138	29	30	0.825581	0.826347	0.173653	0.174419	1.113194	0.739564	1.675581
OV	SBS8	Unknown	150	152	15	22	0.872093	0.91018	0.08982	0.127907	0.549396	0.320947	0.940456
OV	SBS9	PolETA Somatichypermutation	156	148	19	16	0.906977	0.886228	0.113772	0.093023	0.787717	0.484758	1.280016
OV	SBS10a	Polymerase epsilon hyperm	157	145	22	15	0.912791	0.868263	0.131737	0.087209	1.387545	0.881593	2.183867
OV	SBS10b	Polymerase epsilon mutati	151	131	36	21	0.877907	0.784431	0.215569	0.122093	1.523096	1.044954	2.220023
OV	SBS11	Temozolo Chemotherapy	148	139	28	24	0.860465	0.832335	0.167665	0.139535	1.216588	0.808026	1.831731
OV	SBS12	Liver cancer	150	154	13	22	0.872093	0.922156	0.077844	0.127907	0.637161	0.360135	1.127284
OV	SBS13	Endogenous apobec	94	98	69	78	0.546512	0.586826	0.413174	0.453488	0.691941	0.503972	0.950016
OV	SBS14	Mismatchrepair + PolEpsil	154	149	18	18	0.895349	0.892216	0.107784	0.104651	1.265418	0.763538	2.097186
OV	SBS15	Mismatchrepair	107	109	58	65	0.622093	0.652695	0.347305	0.377907	0.868107	0.628945	1.198211
OV	SBS16	Unknown	126	123	44	46	0.732558	0.736527	0.263473	0.267442	1.388362	0.97953	1.96783
OV	SBS17a	Unknown	96	94	73	76	0.55814	0.562874	0.437126	0.44186	0.885088	0.650451	1.204367
OV	SBS17b	Unknown	128	139	28	44	0.744186	0.832335	0.167665	0.255814	0.578189	0.383462	0.8718
OV	SBS18	ReactiveOxy	134	142	25	38	0.77907	0.850299	0.149701	0.22093	1.168964	0.761607	1.7942
OV	SBS19	Unknown	151	143	24	21	0.877907	0.856287	0.143713	0.122093	0.839628	0.543587	1.296895
OV	SBS21	Mismatchrepair	120	104	63	52	0.697674	0.622754	0.377246	0.302326	1.375226	1.00325	1.885119
OV	SBS22	Aristolochic acid	87	79	88	85	0.505814	0.473054	0.526946	0.494186	1.22764	0.90199	1.670862
OV	SBS23	Unknown	145	145	22	27	0.843023	0.868263	0.131737	0.156977	1.359488	0.865068	2.13649
OV	SBS24	Aflatoxin	90	73	94	82	0.523256	0.437126	0.562874	0.476744	1.224458	0.897989	1.669617
OV	SBS25	Chemotherapy	127	124	43	45	0.738372	0.742515	0.257485	0.261628	1.086582	0.764293	1.544776
OV	SBS26	Mismatchrepair	138	123	44	34	0.802326	0.736527	0.263473	0.197674	1.141573	0.807986	1.612885
OV	SBS28	Unknown	134	138	29	38	0.77907	0.826347	0.173653	0.22093	0.763044	0.508438	1.145146
OV	SBS29	Tobacco chewing in Hollst	99	105	62	73	0.575581	0.628743	0.371257	0.424419	0.750038	0.545618	1.031045
OV	SBS20	Mismatchrepair + POLD1mut	127	117	50	45	0.738372	0.700599	0.299401	0.261628	1.478086	1.055361	2.070134
OV	SBS30	BER repair-NTHL1mut	110	100	67	62	0.639535	0.598802	0.401198	0.360465	1.368702	1.001678	1.870208
OV	SBS31	PLChemotherapy	143	146	21	29	0.831395	0.874251	0.125749	0.168605	0.820759	0.51829	1.299748
OV	SBS32	AZA Chemotherapy	148	151	16	24	0.860465	0.904192	0.095808	0.139535	0.622446	0.369844	1.047576
OV	SBS33	Unknown	119	125	42	53	0.69186	0.748503	0.251497	0.30814	0.903095	0.634072	1.286259
OV	SBS34	Unknown	155	149	18	17	0.901163	0.892216	0.107784	0.098837	0.738461	0.450235	1.2112
OV	SBS35	PLChemotherapy	153	151	16	19	0.889535	0.904192	0.095808	0.110465	0.739759	0.438684	1.247465
OV	SBS36	BERrepair MUTY	156	148	19	16	0.906977	0.886228	0.113772	0.093023	0.778159	0.479685	1.262354
OV	SBS37	Unknown	123	103	64	49	0.715116	0.616766	0.383234	0.284884	1.36656	0.995802	1.87536
OV	SBS38	UV	111	118	49	61	0.645349	0.706587	0.293413	0.354651	0.754112	0.539158	1.054763
OV	SBS39	Unknown	56	75	92	116	0.325581	0.449102	0.550898	0.674419	0.554464	0.404336	0.760335
OV	SBS42	Haloalkane	148	144	23	24	0.860465	0.862275	0.137725	0.139535	0.962731	0.609035	1.521837
OV	SBS84	Actind cytidinedeaminase	124	134	33	48	0.72093	0.802395	0.197605	0.27907	0.735027	0.499287	1.082071
OV	SBS85	Actind cytidinedeaminase	162	153	14	10	0.94186	0.916168	0.083832	0.05814	1.428881	0.820506	2.488343
OV	SBS40	Unknown
OV	SBS41	Unknown
OV	SBS44	Mismatchrepair
PAAD	SBS1	Endogenous clock-like age	21	9	68	68	0.235955	0.116883	0.883117	0.764045	1.603868	0.784975	3.277038
PAAD	SBS2	Endogenous Apobec3a	58	39	38	31	0.651685	0.506494	0.493506	0.348315	1.063906	0.665894	1.699814
PAAD	SBS3	Homologous repair	88	77	0	1	0.988764	1	0	0.011236	4.41E−07	0
PAAD	SBS4	Tobacco	81	67	10	8	0.910112	0.87013	0.12987	0.089888	1.382913	0.702847	2.721003
PAAD	SBS6	Mismatchrepair	64	47	30	25	0.719101	0.61039	0.38961	0.280899	1.253116	0.778242	2.017751
PAAD	SBS7a	UV	78	62	15	11	0.876404	0.805195	0.194805	0.123596	1.209366	0.674163	2.169455
PAAD	SBS7b	UV	75	60	17	14	0.842697	0.779221	0.220779	0.157303	1.199749	0.694626	2.072191
PAAD	SBS7c	UV	75	72	5	14	0.842697	0.935065	0.064935	0.157303	0.446106	0.178089	1.11748
PAAD	SBS7d	UV	65	63	14	24	0.730337	0.818182	0.181818	0.269663	0.716118	0.394436	1.300146
PAAD	SBS8	Unknown	73	74	3	16	0.820225	0.961039	0.038961	0.179775	0.178745	0.051427	0.621259
PAAD	SBS9	PolETA Somatichypermutation	88	76	1	1	0.988764	0.987013	0.012987	0.011236	2.053762	0.273648	15.41376
PAAD	SBS10a	Polymerase epsilon hyperm	74	60	17	15	0.831461	0.779221	0.220779	0.168539	0.937699	0.540165	1.627799
PAAD	SBS10b	Polymerase epsilon mutati	59	45	32	30	0.662921	0.584416	0.415584	0.337079	1.230313	0.759816	1.992154
PAAD	SBS11	Temozolo Chemotherapy	77	70	7	12	0.865169	0.909091	0.090909	0.134831	0.703435	0.321589	1.538678
PAAD	SBS12	Liver cancer	72	67	10	17	0.808989	0.87013	0.12987	0.191011	0.557962	0.28222	1.103116
PAAD	SBS13	Endogenous apobec	52	36	41	37	0.58427	0.467532	0.532468	0.41573	1.181033	0.742451	1.878696
PAAD	SBS14	Mismatchrepair + PolEpsil	73	68	9	16	0.820225	0.883117	0.116883	0.179775	0.761522	0.373568	1.552369
PAAD	SBS15	Mismatchrepair	70	48	29	19	0.786517	0.623377	0.376623	0.213483	1.435183	0.893575	2.305068
PAAD	SBS16	Unknown	84	64	13	5	0.94382	0.831169	0.168831	0.05618	1.413855	0.765758	2.610466
PAAD	SBS17a	Unknown	76	55	22	13	0.853933	0.714286	0.285714	0.146067	1.995268	1.172958	3.394066
PAAD	SBS17b	Unknown	79	60	17	10	0.88764	0.779221	0.220779	0.11236	1.464147	0.839251	2.554331
PAAD	SBS18	ReactiveOxy	78	67	10	11	0.876404	0.87013	0.12987	0.123596	1.310043	0.665369	2.57934
PAAD	SBS19	Unknown	69	63	14	20	0.775281	0.818182	0.181818	0.224719	0.983287	0.528394	1.829794
PAAD	SBS21	Mismatchrepair	72	65	12	17	0.808989	0.844156	0.155844	0.191011	0.607175	0.326186	1.13022
PAAD	SBS22	Aristolochic acid	78	67	10	11	0.876404	0.87013	0.12987	0.123596	0.734891	0.365575	1.477303
PAAD	SBS23	Unknown	85	71	6	4	0.955056	0.922078	0.077922	0.044944	1.289827	0.529696	3.140771
PAAD	SBS24	Aflatoxin	79	58	19	10	0.88764	0.753247	0.246753	0.11236	1.372473	0.80523	2.339308
PAAD	SBS25	Chemotherapy	87	76	1	2	0.977528	0.987013	0.012987	0.022472	1.901406	0.255662	14.14109
PAAD	SBS26	Mismatchrepair	82	66	11	7	0.921348	0.857143	0.142857	0.078652	1.715602	0.88974	3.308033
PAAD	SBS28	Unknown	81	65	12	8	0.910112	0.844156	0.155844	0.089888	1.223074	0.652669	2.291987
PAAD	SBS29	Tobacco chewing in Hollst	59	49	28	30	0.662921	0.636364	0.363636	0.337079	0.995468	0.618291	1.602735
PAAD	SBS20	Mismatchrepair + POLD1mut	79	69	8	10	0.88764	0.896104	0.103896	0.11236	1.074822	0.510595	2.262541
PAAD	SBS30	BER repair-NTHL1mut	73	54	23	16	0.820225	0.701299	0.298701	0.179775	1.172404	0.700396	1.962506
PAAD	SBS31	PLChemotherapy	79	69	8	10	0.88764	0.896104	0.103896	0.11236	0.660311	0.301263	1.447273
PAAD	SBS32	AZA Chemotherapy	77	71	6	12	0.865169	0.922078	0.077922	0.134831	0.595623	0.240788	1.473357
PAAD	SBS33	Unknown	82	65	12	7	0.921348	0.844156	0.155844	0.078652	1.41726	0.738242	2.720822
PAAD	SBS34	Unknown	79	65	12	10	0.88764	0.844156	0.155844	0.11236	1.536612	0.811448	2.909833
PAAD	SBS35	PLChemotherapy	78	70	7	11	0.876404	0.909091	0.090909	0.123596	0.687796	0.312022	1.516121
PAAD	SBS36	BERrepair MUTY	70	67	10	19	0.786517	0.87013	0.12987	0.213483	0.785028	0.391195	1.575351
PAAD	SBS37	Unknown	80	68	9	9	0.898876	0.883117	0.116883	0.101124	0.852752	0.421758	1.724182
PAAD	SBS38	UV	76	62	15	13	0.853933	0.805195	0.194805	0.146067	1.15544	0.64822	2.059549
PAAD	SBS39	Unknown	66	62	15	23	0.741573	0.805195	0.194805	0.258427	0.577062	0.319624	1.041852
PAAD	SBS39	Unknown	66	62	15	23	0.741573	0.805195	0.194805	0.258427	0.577062	0.319624	1.041852
PAAD	SBS42	Haloalkane	82	65	12	7	0.921348	0.844156	0.155844	0.078652	2.009717	1.058165	3.816951
PAAD	SBS84	Actind cytidinedeaminase	82	75	2	7	0.921348	0.974026	0.025974	0.078652	0.697663	0.168587	2.887142
PAAD	SBS85	Actind cytidinedeaminase	80	69	8	9	0.898876	0.896104	0.103896	0.101124	0.815248	0.380929	1.744761
PAAD	SBS40	Unknown
PAAD	SBS41	Unknown
PAAD	SBS44	Mismatchrepair
SARC	SBS1	Endogenous clock-like age	138	69	2	23	0.857143	0.971831	0.028169	0.142857	0.15965	0.038532	0.661487
SARC	SBS2	Endogenous Apobec3a	135	54	17	26	0.838509	0.760563	0.239437	0.161491	1.184972	0.676195	2.076559
SARC	SBS3	Homologous repair	143	60	11	18	0.888199	0.84507	0.15493	0.111801	0.992807	0.517246	1.905603
SARC	SBS4	Tobacco	112	54	17	49	0.695652	0.760563	0.239437	0.304348	0.634815	0.364092	1.106838
SARC	SBS6	Mismatchrepair	119	49	22	42	0.73913	0.690141	0.309859	0.26087	1.392156	0.834756	2.321756
SARC	SBS7a	UV	110	57	14	51	0.68323	0.802817	0.197183	0.31677	0.664181	0.369659	1.193361
SARC	SBS7b	UV	112	55	16	49	0.695652	0.774648	0.225352	0.304348	0.693083	0.394923	1.21635
SARC	SBS7c	UV	133	57	14	28	0.826087	0.802817	0.197183	0.173913	1.187036	0.65378	2.155242
SARC	SBS7d	UV	132	53	18	29	0.819876	0.746479	0.253521	0.180124	1.744033	0.997159	3.050318
SARC	SBS8	Unknown	137	63	8	24	0.850932	0.887324	0.112676	0.149068	0.735581	0.350529	1.543609
SARC	SBS9	PolETA Somatichypermutation	155	70	1	6	0.962733	0.985915	0.014085	0.037267	0.853992	0.117746	6.193871
SARC	SBS10a	Polymerase epsilon hyperm	140	65	6	21	0.869565	0.915493	0.084507	0.130435	0.648344	0.280057	1.500948
SARC	SBS10b	Polymerase epsilon mutati	121	41	30	40	0.751553	0.577465	0.422535	0.248447	1.626911	1.010595	2.61909
SARC	SBS11	Temozolo Chemotherapy	134	66	5	27	0.832298	0.929577	0.070423	0.167702	0.396038	0.158834	0.987483
SARC	SBS12	Liver cancer	141	66	5	20	0.875776	0.929577	0.070423	0.124224	0.587305	0.236119	1.460817
SARC	SBS13	Endogenous apobec	140	58	13	21	0.869565	0.816901	0.183099	0.130435	1.419913	0.768776	2.622549
SARC	SBS14	Mismatchrepair + PolEpsil	118	58	13	43	0.732919	0.816901	0.183099	0.267081	0.612102	0.333885	1.122149
SARC	SBS15	Mismatchrepair	141	65	6	20	0.875776	0.915493	0.084507	0.124224	0.679326	0.293611	1.571754
SARC	SBS16	Unknown	140	55	16	21	0.869565	0.774648	0.225352	0.130435	1.679573	0.960448	2.937136
SARC	SBS17a	Unknown	104	48	23	57	0.645963	0.676056	0.323944	0.354037	0.792763	0.478056	1.314643
SARC	SBS17b	Unknown	137	57	14	24	0.850932	0.802817	0.197183	0.149068	1.558552	0.860717	2.822165
SARC	SBS18	ReactiveOxy	142	64	7	19	0.881988	0.901408	0.098592	0.118012	0.73969	0.337271	1.622262
SARC	SBS19	Unknown	102	37	34	59	0.63354	0.521127	0.478873	0.36646	1.444351	0.90362	2.30866
SARC	SBS21	Mismatchrepair	145	62	9	16	0.900621	0.873239	0.126761	0.099379	1.387044	0.688313	2.795082
SARC	SBS22	Aristolochic acid	120	40	31	41	0.745342	0.56338	0.43662	0.254658	2.043352	1.275126	3.27441
SARC	SBS23	Unknown	141	62	9	20	0.875776	0.873239	0.126761	0.124224	0.803231	0.397322	1.623821
SARC	SBS24	Aflatoxin	98	36	35	63	0.608696	0.507042	0.492958	0.391304	1.443093	0.905187	2.300647
SARC	SBS25	Chemotherapy	150	69	2	11	0.931677	0.971831	0.028169	0.068323	0.429445	0.104555	1.763892
SARC	SBS26	Mismatchrepair	136	59	12	25	0.84472	0.830986	0.169014	0.15528	1.050773	0.563943	1.957866
SARC	SBS28	Unknown	141	65	6	20	0.875776	0.915493	0.084507	0.124224	0.751723	0.323086	1.749029
SARC	SBS29	Tobacco chewing in Hollst	124	54	17	37	0.770186	0.760563	0.239437	0.229814	1.185889	0.681574	2.063361
SARC	SBS22	Mismatchrepair + POLD1mut	124	62	9	37	0.770186	0.873239	0.126761	0.229814	0.462591	0.229072	0.934164
SARC	SBS30	BER repair-NTHL1mut	111	42	29	50	0.689441	0.591549	0.408451	0.310559	1.431514	0.885935	2.313073
SARC	SBS31	PLChemotherapy	135	55	16	26	0.838509	0.774648	0.225352	0.161491	1.306709	0.734321	2.32526
SARC	SBS32	AZA Chemotherapy	111	45	26	50	0.689441	0.633803	0.366197	0.310559	1.202873	0.738976	1.957982
SARC	SBS33	Unknown	135	62	9	26	0.838509	0.873239	0.126761	0.161491	0.8116	0.401682	1.63984
SARC	SBS34	Unknown	145	60	11	16	0.900621	0.84507	0.15493	0.099379	1.372633	0.718951	2.620652
SARC	SBS35	PLChemotherapy	138	64	7	23	0.857143	0.901408	0.098592	0.142857	0.633165	0.288065	1.391694
SARC	SBS36	BERrepair MUTY	141	62	9	20	0.875776	0.873239	0.126761	0.124224	0.780451	0.384495	1.584167
SARC	SBS37	Unknown	136	56	15	25	0.84472	0.788732	0.211268	0.15528	1.355318	0.764497	2.40274
SARC	SBS38	UV	123	46	25	38	0.763975	0.647887	0.352113	0.236025	1.650469	1.011447	2.693218
SARC	SBS39	Unknown	66	17	54	95	0.409938	0.239437	0.760563	0.590062	1.901288	1.092687	3.308263
SARC	SBS42	Haloalkane	140	57	14	21	0.869565	0.802817	0.197183	0.130435	1.627957	0.905034	2.928338
SARC	SBS84	Actind cytidinedeaminase	145	57	14	16	0.900621	0.802817	0.197183	0.099379	1.810656	0.996734	3.289219
SARC	SBS85	Actind cytidinedeaminase	133	64	7	28	0.826087	0.901408	0.098592	0.173913	0.673044	0.3028	1.495998
SARC	SBS40	Unknown
SARC	SBS41	Unknown
SARC	SBS44	Mismatchrepair
SKCM	SBS1	Endogenous clock-like age	142	104	82	116	0.550388	0.55914	0.44086	0.449612	0.682458	0.505569	0.921237
SKCM	SBS2	Endogenous Apobec3a	236	160	26	22	0.914729	0.860215	0.139785	0.085271	1.492814	0.975604	2.284221
SKCM	SBS3	Homologous repair	254	181	5	4	0.984496	0.973118	0.026882	0.015504	1.323059	0.53088	3.297328
SKCM	SBS4	Tobacco	245	169	17	13	0.949612	0.908602	0.091398	0.050388	1.947576	1.168027	3.247402
SKCM	SBS6	Mismatchrepair	168	128	58	90	0.651163	0.688172	0.311828	0.348837	0.775711	0.562587	1.069573
SKCM	SBS7a	UV	67	72	114	191	0.25969	0.387097	0.612903	0.74031	0.526015	0.385888	0.717026
SKCM	SBS7b	UV	51	51	135	207	0.197674	0.274194	0.725806	0.802326	0.450604	0.318166	0.638169
SKCM	SBS7c	UV	135	104	82	123	0.523256	0.55914	0.44086	0.476744	0.660867	0.488083	0.894817
SKCM	SBS7d	UV	178	104	82	80	0.689922	0.55914	0.44086	0.310078	1.449075	1.07895	1.946168
SKCM	SBS8	Unknown	258	185	1	0	1	0.994624	0.005376	0	5.686784	0.690582	46.82935
SKCM	SBS9	PolETA Somatichypermutation	257	185	1	1	0.996124	0.994624	0.005376	0.003876	0.488467	0.064537	3.697121
SKCM	SBS10a	Polymerase epsilon hyperm	255	183	3	3	0.988372	0.983871	0.016129	0.011628	2.052614	0.650623	6.47567
SKCM	SBS10b	Polymerase epsilon mutati	111	97	89	147	0.430233	0.521505	0.478495	0.569767	0.611344	0.451711	0.82739
SKCM	SBS11	Temozolo Chemotherapy	226	160	26	32	0.875969	0.860215	0.139785	0.124031	0.96235	0.632033	1.4653
SKCM	SBS12	Liver cancer	253	177	9	5	0.98062	0.951613	0.048387	0.01938	1.362379	0.690655	2.687418
SKCM	SBS13	Endogenous apobec	200	127	59	58	0.775194	0.682796	0.317204	0.224806	1.625223	1.176426	2.245233
SKCM	SBS14	Mismatchrepair + PolEpsil	250	180	6	8	0.968992	0.967742	0.032258	0.031008	0.608634	0.268454	1.379885
SKCM	SBS15	Mismatchrepair	230	165	21	28	0.891473	0.887097	0.112903	0.108527	1.191855	0.743525	1.910518
SKCM	SBS16	Unknown	256	178	8	2	0.992248	0.956989	0.043011	0.007752	1.351077	0.660446	2.763902
SKCM	SBS17a	Unknown	134	108	78	124	0.51938	0.580645	0.419355	0.48062	0.614901	0.455796	0.829546
SKCM	SBS17b	Unknown	183	114	72	75	0.709302	0.612903	0.387097	0.290698	1.239193	0.917113	1.674382
SKCM	SBS18	ReactiveOxy	254	180	6	4	0.984496	0.967742	0.032258	0.015504	0.724301	0.316012	1.660103
SKCM	SBS19	Unknown	228	167	19	30	0.883721	0.897849	0.102151	0.116279	0.75981	0.468753	1.231587
SKCM	SBS21	Mismatchrepair	208	150	36	50	0.806202	0.806452	0.193548	0.193798	0.779914	0.535877	1.135086
SKCM	SBS22	Aristolochic acid	203	144	42	55	0.786822	0.774194	0.225806	0.213178	1.11454	0.78552	1.581373
SKCM	SBS23	Unknown	200	140	46	58	0.775194	0.752688	0.247312	0.224806	1.140802	0.815032	1.596784
SKCM	SBS24	Aflatoxin	218	161	25	40	0.844961	0.865591	0.134409	0.155039	1.191448	0.771528	1.839919
SKCM	SBS25	Chemotherapy	258	185	1	0	1	0.994624	0.005376	0	13.37649	1.770312	101.0728
SKCM	SBS26	Mismatchrepair	211	148	38	47	0.817829	0.795699	0.204301	0.182171	0.868621	0.60511	1.246885
SKCM	SBS28	Unknown	251	183	3	7	0.972868	0.983871	0.016129	0.027132	0.891201	0.283173	2.804781
SKCM	SBS29	Tobacco chewing in Hollst	254	184	2	4	0.984496	0.989247	0.010753	0.015504	0.578551	0.129795	2.578855
SKCM	SBS20	Mismatchrepair + POLD1mut	224	169	17	34	0.868217	0.908602	0.091398	0.131783	0.826792	0.497866	1.37303
SKCM	SBS30	BER repair-NTHL1mut	206	139	47	52	0.79845	0.747312	0.252688	0.20155	1.262853	0.901787	1.768484
SKCM	SBS31	PLChemotherapy	235	161	25	23	0.910853	0.865591	0.134409	0.089147	1.701139	1.105879	2.61681
SKCM	SBS32	AZA Chemotherapy	250	176	10	8	0.968992	0.946237	0.053763	0.031008	1.511448	0.792042	2.884286
SKCM	SBS33	Unknown	218	165	21	40	0.844961	0.887097	0.112903	0.155039	0.812415	0.511906	1.289335
SKCM	SBS34	Unknown	249	172	14	9	0.965116	0.924731	0.075269	0.034884	1.940127	1.109363	3.393022
SKCM	SBS35	PLChemotherapy	219	157	29	39	0.848837	0.844086	0.155914	0.151163	1.205954	0.800898	1.815867
SKCM	SBS36	BERrepair MUTY	250	180	6	8	0.968992	0.967742	0.032258	0.031008	0.937069	0.412246	2.130036
SKCM	SBS37	Unknown	250	177	9	8	0.968992	0.951613	0.048387	0.031008	1.366084	0.691927	2.697083
SKCM	SBS38	UV	227	171	15	31	0.879845	0.919355	0.080645	0.120155	0.676967	0.393365	1.165036
SKCM	SBS39	Unknown	212	159	27	46	0.821705	0.854839	0.145161	0.178295	0.566338	0.372614	0.860779
SKCM	SBS42	Haloalkane	221	157	29	37	0.856589	0.844086	0.155914	0.143411	1.191907	0.796057	1.784601
SKCM	SBS84	Actind cytidinedeaminase	238	168	18	20	0.922481	0.903226	0.096774	0.077519	1.174978	0.717141	1.925107
SKCM	SBS85	Actind cytidinedeaminase	253	181	5	5	0.98062	0.973118	0.026882	0.01938	1.574025	0.640147	3.870287
SKCM	SBS40	Unknown
SKCM	SBS40	Unknown
SKCM	SBS41	Unknown
SKCM	SBS44	Mismatchrepair
STAD	SBS1	Endogenous clock-like age	158	73	25	121	0.566308	0.744898	0.255102	0.433692	0.531045	0.333366	0.845943
STAD	SBS2	Endogenous Apobec3a	236	88	10	43	0.845878	0.897959	0.102041	0.154122	0.516728	0.263919	1.011703
STAD	SBS3	Homologous repair	268	91	7	11	0.960573	0.928571	0.071429	0.039427	1.311819	0.600535	2.865561
STAD	SBS4	Tobacco	232	85	13	47	0.831541	0.867347	0.132653	0.168459	0.672619	0.371116	1.219069
STAD	SBS6	Mismatchrepair	192	82	16	87	0.688172	0.836735	0.163265	0.311828	0.45336	0.262001	0.784482
STAD	SBS7a	UV	195	51	47	84	0.698925	0.520408	0.479592	0.301075	1.690301	1.124845	2.540011
STAD	SBS7b	UV	169	71	27	110	0.605735	0.72449	0.27551	0.394265	0.569586	0.360672	0.899511
STAD	SBS7c	UV	245	81	17	34	0.878136	0.826531	0.173469	0.121864	1.339128	0.788672	2.273778
STAD	SBS7d	UV	245	81	17	34	0.878136	0.826531	0.173469	0.121864	1.763232	1.039056	2.992126
STAD	SBS8	Unknown	221	67	31	58	0.792115	0.683673	0.316327	0.207885	1.64977	1.056313	2.576643
STAD	SBS9	PolETA Somatichypermutation	270	95	3	9	0.967742	0.969388	0.030612	0.032258	0.902313	0.277407	2.93492
STAD	SBS10a	Polymerase epsilon hyperm	216	69	29	63	0.774194	0.704082	0.295918	0.225806	1.449412	0.926367	2.26778
STAD	SBS10b	Polymerase epsilon mutati	196	86	12	83	0.702509	0.877551	0.122449	0.297491	0.358713	0.194138	0.662801
STAD	SBS11	Temozolo Chemotherapy	262	88	10	17	0.939068	0.897959	0.102041	0.060932	1.696239	0.873695	3.293173
STAD	SBS12	Liver cancer	235	75	23	44	0.842294	0.765306	0.234694	0.157706	1.62552	1.007189	2.623457
STAD	SBS13	Endogenous apobec	198	76	22	81	0.709677	0.77551	0.22449	0.290323	0.651343	0.399501	1.061945
STAD	SBS14	Mismatchrepair + PolEpsil	236	86	12	43	0.845878	0.877551	0.122449	0.154122	0.6576	0.352705	1.22606
STAD	SBS15	Mismatchrepair	240	92	6	39	0.860215	0.938776	0.061224	0.139785	0.390017	0.169171	0.899166
STAD	SBS16	Unknown	237	93	5	42	0.849462	0.94898	0.05102	0.150538	0.348821	0.140857	0.863826
STAD	SBS17	Unknown	204	64	34	75	0.731183	0.653061	0.346939	0.268817	1.142538	0.740985	1.761702
STAD	SBS17	Unknown	237	79	19	42	0.849462	0.806122	0.193878	0.150538	1.33957	0.799462	2.244568
STAD	SBS18	ReactiveOxy	193	66	32	86	0.691756	0.673469	0.326531	0.308244	1.158349	0.751285	1.78597
STAD	SBS19	Unknown	238	86	12	41	0.853047	0.877551	0.122449	0.146953	0.826889	0.44238	1.545604
STAD	SBS21	Mismatchrepair	241	90	8	38	0.863799	0.918367	0.081633	0.136201	0.473979	0.22867	0.982446
STAD	SBS22	Aristolochic acid	183	59	39	96	0.655914	0.602041	0.397959	0.344086	1.478127	0.979722	2.230083
STAD	SBS23	Unknown	262	96	2	17	0.939068	0.979592	0.020408	0.060932	0.520296	0.127169	2.128723
STAD	SBS24	Aflatoxin	251	87	11	28	0.899642	0.887755	0.112245	0.100358	1.214573	0.638974	2.308684
STAD	SBS25	Chemotherapy	246	90	8	33	0.88172	0.918367	0.081633	0.11828	0.718158	0.342922	1.50399
STAD	SBS26	Mismatchrepair	226	86	12	53	0.810036	0.877551	0.122449	0.189964	0.516085	0.277004	0.961514
STAD	SBS28	Unknown	247	89	9	32	0.885305	0.908163	0.091837	0.114695	0.735689	0.36679	1.475605
STAD	SBS29	Tobacco chewing in Hollst	169	74	24	110	0.605735	0.755102	0.244898	0.394265	0.552913	0.346481	0.882335
STAD	SBS20	Mismatchrepair + POLD1mut	219	82	16	60	0.784946	0.836735	0.163265	0.215054	0.60074	0.342842	1.052637
STAD	SBS30	BER repair-NTHL1mut	245	83	15	34	0.878136	0.846939	0.153061	0.121864	1.129391	0.645952	1.974644
STAD	SBS31	PLChemotherapy	213	80	18	66	0.763441	0.816327	0.183673	0.236559	0.723888	0.422355	1.240695
STAD	SBS32	AZA Chemotherapy	247	90	8	32	0.885305	0.918367	0.081633	0.114695	0.717479	0.345356	1.490566
STAD	SBS33	Unknown	170	68	30	109	0.609319	0.693878	0.306122	0.390681	0.599262	0.385692	0.931092
STAD	SBS34	Unknown	232	86	12	47	0.831541	0.877551	0.122449	0.168459	0.678022	0.368468	1.247635
STAD	SBS35	PLChemotherapy	221	84	14	58	0.792115	0.857143	0.142857	0.207885	0.712483	0.401196	1.265296
STAD	SBS36	BERrepair MUTY	244	82	16	35	0.874552	0.836735	0.163265	0.125448	1.190653	0.68153	2.080106
STAD	SBS37	Unknown	236	84	14	43	0.845878	0.857143	0.142857	0.154122	0.829077	0.46712	1.471502
STAD	SBS38	UV	221	74	24	58	0.792115	0.755102	0.244898	0.207885	1.27652	0.79526	2.049019
STAD	SBS39	Unknown	103	30	68	176	0.369176	0.306122	0.693878	0.630824	1.37563	0.88816	2.13065
STAD	SBS42	Haloalkane	269	94	4	10	0.964158	0.959184	0.040816	0.035842	1.126325	0.409118	3.100832
STAD	SBS84	Actind cytidinedeaminase	255	90	8	24	0.913978	0.918367	0.081633	0.086022	1.134929	0.541858	2.377122
STAD	SBS85	Actind cytidinedeaminase	255	88	10	24	0.913978	0.897959	0.102041	0.086022	1.264047	0.653662	2.444405
STAD	SBS40	Unknown
STAD	SBS41	Unknown
STAD	SBS44	Mismatchrepair
UCEC	SBS1	Endogenous clock-like age	230	43	14	234	0.49569	0.754386	0.245614	0.50431	0.303877	0.16276	0.567346
UCEC	SBS2	Endogenous Apobec3a	304	30	27	160	0.655172	0.526316	0.473684	0.344828	1.500275	0.871621	2.582342
UCEC	SBS3	Homologous repair	450	54	3	14	0.969828	0.947368	0.052632	0.030172	1.468458	0.452606	4.764342
UCEC	SBS4	Tobacco	378	49	8	86	0.814655	0.859649	0.140351	0.185345	0.807646	0.381574	1.709479
UCEC	SBS6	Mismatchrepair	395	56	1	69	0.851293	0.982456	0.017544	0.148707	0.064567	0.008904	0.468204
UCEC	SBS7a	UV	302	34	23	162	0.650862	0.596491	0.403509	0.349138	1.231566	0.715176	2.120812
UCEC	SBS7c	UV	403	54	3	61	0.868534	0.947368	0.052632	0.131466	0.306673	0.095188	0.988031
UCEC	SBS7d	UV	392	50	7	72	0.844828	0.877193	0.122807	0.155172	0.877847	0.395833	1.946819
UCEC	SBS8	Unknown	390	43	14	74	0.840517	0.754386	0.245614	0.159483	1.750593	0.941599	3.254649
UCEC	SBS9	PolETA Somatichypermutation	443	57	0	21	0.954741	1	0	0.045259	1.08E−06	0
UCEC	SBS10	Polymerase epsilon hyperm	399	56	1	65	0.859914	0.982456	0.017544	0.140086	0.063907	0.008739	0.467363
UCEC	SBS10	Polymerase epsilon mutati	386	55	2	78	0.831897	0.964912	0.035088	0.168103	0.130551	0.031422	0.542416
UCEC	SBS11	Temozolo Chemotherapy	400	52	5	64	0.862069	0.912281	0.087719	0.137931	0.511451	0.204055	1.281925
UCEC	SBS12	Liver cancer	397	45	12	67	0.855603	0.789474	0.210526	0.144397	1.546494	0.81199	2.94541
UCEC	SBS13	Endogenous apobec	322	29	28	142	0.693966	0.508772	0.491228	0.306034	1.761385	1.024621	3.027926
UCEC	SBS14	Mismatchrepair + PolEpsil	371	54	3	93	0.799569	0.947368	0.052632	0.200431	0.128418	0.039269	0.419955
UCEC	SBS15	Mismatchrepair	370	53	4	94	0.797414	0.929825	0.070175	0.202586	0.225888	0.080229	0.636001
UCEC	SBS16	Unknown	325	30	27	139	0.700431	0.526316	0.473684	0.299569	2.174137	1.278438	3.697381
UCEC	SBS17a	Unknown	313	50	7	151	0.674569	0.877193	0.122807	0.325431	0.285819	0.127618	0.640131
UCEC	SBS17b	Unknown	397	54	3	67	0.855603	0.947368	0.052632	0.144397	0.218838	0.067359	0.71097
UCEC	SBS18	ReactiveOxy	398	43	14	66	0.857759	0.754386	0.245614	0.142241	1.98249	1.083737	3.626587
UCEC	SBS19	Unknown	355	49	8	109	0.765086	0.859649	0.140351	0.234914	0.717542	0.337949	1.523505
UCEC	SBS21	Mismatchrepair	366	48	9	98	0.788793	0.842105	0.157895	0.211207	0.492341	0.237949	1.018704
UCEC	SBS22	Aristolochic acid	409	46	11	55	0.881466	0.807018	0.192982	0.118534	1.973855	1.021067	3.815715
UCEC	SBS23	Unknown	411	48	9	53	0.885776	0.842105	0.157895	0.114224	1.078653	0.528435	2.20177
UCEC	SBS24	Aflatoxin	332	34	23	132	0.715517	0.596491	0.403509	0.284483	1.635475	0.949361	2.817451
UCEC	SBS25	Chemotherapy	437	55	2	27	0.94181	0.964912	0.035088	0.05819	0.85212	0.206278	3.520058
UCEC	SBS26	Mismatchrepair	298	46	11	166	0.642241	0.807018	0.192982	0.357759	0.424395	0.214953	0.83791
UCEC	SBS28	Unknown	373	52	5	91	0.803879	0.912281	0.087719	0.196121	0.43521	0.172525	1.097854
UCEC	SBS29	Tobacco chewing in Hollst	301	31	26	163	0.648707	0.54386	0.45614	0.351293	1.822548	1.066883	3.113447
UCEC	SBS20	Mismatchrepair + POLD1mut	403	55	2	61	0.868534	0.964912	0.035088	0.131466	0.17879	0.043454	0.735631
UCEC	SBS30	BER repair-NTHL1mut	419	46	11	45	0.903017	0.807018	0.192982	0.096983	1.927281	0.995245	3.732161
UCEC	SBS31	PLChemotherapy	394	49	8	70	0.849138	0.859649	0.140351	0.150862	0.828878	0.391941	1.752913
UCEC	SBS32	AZA Chemotherapy	412	53	4	52	0.887931	0.929825	0.070175	0.112069	0.490073	0.175761	1.366465
UCEC	SBS33	Unknown	300	51	6	164	0.646552	0.894737	0.105263	0.353448	0.150823	0.062906	0.36161
UCEC	SBS34	Unknown	354	36	21	110	0.762931	0.631579	0.368421	0.237069	1.938963	1.130088	3.326801
UCEC	SBS35	PLChemotherapy	402	50	7	62	0.866379	0.877193	0.122807	0.133621	0.973323	0.440499	2.150646
UCEC	SBS36	BERrepair MUTY	402	50	7	62	0.866379	0.877193	0.122807	0.133621	0.931541	0.422134	2.055672
UCEC	SBS37	Unknown	412	54	3	52	0.887931	0.947368	0.052632	0.112069	0.427947	0.132367	1.38357
UCEC	SBS38	UV	399	55	2	65	0.859914	0.964912	0.035088	0.140086	0.204082	0.049504	0.841339
UCEC	SBS39	Unknown	284	19	38	180	0.612069	0.333333	0.666667	0.387931	2.710644	1.540951	4.768219
UCEC	SBS42	Haloalkane	390	42	15	74	0.840517	0.736842	0.263158	0.159483	1.44319	0.799695	2.60449
UCEC	SBS84	Actind cytidinedeaminase	417	49	8	47	0.898707	0.859649	0.140351	0.101293	1.174637	0.555513	2.483782
UCEC	SBS85	Actind cytidinedeaminase	435	54	3	29	0.9375	0.947368	0.052632	0.0625	0.714982	0.223157	2.290762
UCEC	SBS40	Unknown
UCEC	SBS41	Unknown
UCEC	SBS44	Mismatchrepair
UCEC	SBS7b	UV
indicates data missing or illegible when filed

Abbreviations

• • BER—Base Excision Repair
  • AID—Activation-induced cytidine deaminase
  • *All hazard ratios adjusted for diagnosis age, sex (except gender-specific cancers), and cancer stage. The latter was omitted when the signature was associated with stage, as stage was then considered to potentially be on the causal pathway between exposure (signature) and outcome. Immortal person-time adjustments were incorporated.

Among endogenous mutation measures (FIGS. 1 and 2), the most common etiology of the mutational signatures identified was a clock-like signature associated with aging (SBS1), implicated in survival of 6 cancers, including Colon adenocarcinoma (COAD), LGG, Liver hepatocellular carcinoma (LIHC), OV, Stomach adenocarcinoma (STAD), and Uterine Corpus Endometrial Carcinoma (UCEC) (Table 2 and FIG. 1). The effect of the aging signature on survival was mixed, in that risk of cancer-specific mortality was reduced among participants with COAD, STAD and UCEC cancers, but elevated up to 5.5-fold in other cancers. Two signatures (SBS2 and SBS13) of deregulated APOBEC-related cytosine deamination activity were both associated with reduced mortality in BLCA patients, but in those with LGG, LIHC, and Skin Cutaneous Melanoma (SKCM) cancers, risk of disease-specific mortality was elevated up to 6-fold. Defects in DNA repair mechanisms that may have contributed to altered survival include several signatures of mismatch repair (SBS6, 15, 20, 26) in BRCA, COAD, LIHC, and STAD tumors, in which LIHC and STAD patients with SBS6 experienced a reduced mortality risk, but risks were elevated otherwise. A base excision repair signature (SBS30) was related to 2.5 and 6-fold increased mortality, respectively, in COAD and LGG. Polymerase epsilon, which acts in both replication and DNA recombination, also facilitates completion of base excision and nucleotide excision repair, thus signatures of defective polymerase epsilon (SBS10a, SBS10b) in BLCA, BRCA, LGG, SKCM, or STAD survival could be attributed to these several cellular mechanisms. In addition to the above, a further endogenous process implicated in DSS is activation-induced cytidine deaminase in 3.5 and 5-fold increased risks of disease-specific mortality in LIHC and Head and Neck squamous cell carcinoma (HNSC).

Among signatures of exogenous mutagenic agents (FIGS. 3 and 4), that associated with aristolochic acid, an herbal medicine component (SBS22), was related to reduced mortality in BLCA, but to 2 to 3.8-fold increased mortality in COAD, LGG, and SARC (Table 2). Ultraviolet (UV) exposure, captured by the SBS7a, 7b, 7c, and SBS38 signatures, differed in relationship to mortality by type of cancer and signature, with BLCA patients experiencing both reduced and increased risks, LIHC patients only increased risks, while all risks were reduced in SKCM patients. Those with signatures of tobacco exposure (Hollstein et al., 2017) (SBS4, SBS29) had increased risks of cancer mortality in BRCA (4-fold), LGG (2.2 to 2.8-fold), and SKCM (3-fold). COAD, LGG, LUSC, and SKCM patients bearing a signature of previous chemotherapy treatment (SBS11, SBS25, SBS31) had 4 to 5-fold elevated risks of mortality due to their respective cancers, while chemotherapy-related mortality was elevated 2.5-fold in BLCA. CESC and COAD-specific mortality were increased 3-8-fold among those whose cancers demonstrated the mutational signatures of haloalkanes (SBS42), an organic solvent exposure incurred occupationally (Mimaki et al., 2016). Aflatoxin mutagenesis (SBS24) was associated with a 3-fold increased risk of LGG-specific mortality and a greater than 13-fold increased risk of mortality among those with LIHC. Among COAD patients, those with a signature of reactive oxygen species (SBS18), considered a metabolite of carcinogenic exposures but also generated endogenously, had a 3.5-fold increased risk of disease-specific mortality.

To evaluate one possible mechanism whereby mutational signatures might influence survival, the relationship between signature and stage within each cancer (Table 2) was assessed. Of the 46 evaluable relationships, 10 were also associated with stage at diagnosis when assessed using continuous, discrete, or binary survival cutpoint measures. However, many with strong relationships with DSS (continuous or discrete, and binary cutoff) were not (COAD and SBS26 (mismatch repair), LIHC and SBS1 (Endogenous clock-like age), SKCM and SBS7b (UV), and SKCM and SBS10b (Polymerase Epsilon) are among those).

TABLE 3A
Relative risk for diagnosis with stage 3 or 4 disease, relative to stage 1,
according to mutational signatures related to disease-specific survival.

					Maxstat
			Continuous	Discrete	Relative
Cancer*	Signature	Signature Description	(p-value**)	(p-value**)	Risk***	Lower CI	Upper CI

BRCA	SBS12	Liver-cancer related	0.0325	0.61	1.3438	1.0396	1.7368
	SBS22	Aristolochic acid	0.0213	0.14	0.6237	0.4321	0.9004
CESC	_all—	Stage missing
COAD	SBS1	Endogenous clock-like age	0.016	0.0155	0.6250	0.4866	0.8026
	SBS6	Mismatch Repair	0.0055	0.0075	0.6076	0.4438	0.8318
	SBS14	Mismatchrepair + PolEpsilon	0.0063	0.0021	0.4786	0.2924	0.7836
	SBS15	Mismatch repair	0.0034	0.0185	0.4181	0.237	0.7376
	SBS20	Mismatchrepair + POLD1mut	0.0021	0.0041	0.6123	0.4247	0.8826
	SBS33	Unknown	0.0012	0.0018	0.7148	0.5332	0.9583
	SBS39	Unknown	0.2244	0.9573	1.3751	1.038	1.8218
HNSC	SBS2	Endogenous Apobec3a	0.1445	0.3949	1.1640	1.0163	1.3332
	SBS4	Tobacco	0.1959	0.732	1.1444	1.0195	1.2845
	SBS24	Aflatoxin	0.2453	0.375	1.1306	1.0242	1.248
	SBS29	Tobacco	0.1974	0.2593	1.1500	1.0409	1.2705
	SBS31	PLChemotherapy	0.2613	0.5023	1.1273	1.0007	1.2699
LGG	_all—	Stage missing
LIHC	SBS24	Aflatoxin	0.0715	0.0474	1.7451	1.122	2.714
	SBS25	Chemotherapy	0.7238	0.793	1.5335	1.0309	2.2814
	SBS84	Actind cytidine deaminase	0.0088	0.2167	1.7365	1.1284	2.6724
LUAD	SBS25	Chemotherapy	0.3480	0.437	1.5546	1.0058	2.4030
	SBS29	Tobacco	0.0068	0.0882	1.5384	1.0089	2.3458
LUSC	SBS1	Endogenous clock-like age	0.2526	0.5205	3.9657	1.0116	15.5467
	SBS23	Unknown	0.3356	0.5686	2.2129	1.3928	3.5159
	SBS25	Chemotherapy	0.0411	0.0949	1.6952	1.0646	2.6992
OV	_all—	Stage missing
PAAD	SBS32	AZA Chemotherapy	0.1111	0.8842	4.2668	1.2007	15.163
SARC	_all—	Stage missing
SKCM	SBS4	Tobacco	0.0039	0.9926	1.6503	1.271	2.1429
	SBS7c	Ultraviolet	0.3486	0.8503	0.7935	0.6377	0.9874
	SBS10b	Polymerase epsilon	0.7141	0.6232	0.8091	0.656	0.998
		mutation
	SBS36	Base excision repair MUTY	0.3444	0.9259	1.5259	1.0355	2.2485
	SBS38	Ultraviolet	0.0334	0.0264	0.5749	0.3437	0.9618
STAD	SBS1	Endogenous clock-like age	0.0106	0.7954	0.8651	0.6997	1.0697
	SBS7c	Ultraviolet	0.0154	0.7877	1.2383	0.9872	1.5531
	SBS16	Unknown	0.0308	0.6479	0.6958	0.4827	1.0000
	SBS19	Unknown	0.0072	0.1246	1.0700	0.8730	1.3115
	SBS20	Mismatchrepair + POLD1mut	0.0845	0.0143	0.8688	0.6594	1.1447
	SBS26	Mismatchrepair	0.0303	0.6375	0.8767	0.6264	1.2190
	SBS29	Tobacco	0.0500	0.1886	0.9649	0.7883	1.1810
	SBS34	Unknown	0.0089	0.7431	1.1945	0.9546	1.4946
	SBS39	Unknown	0.0280	0.4674	1.1622	0.9439	1.4309
UCEC	_all—	Stage missing
All relationships adjusted for age and gender, except gender omitted for BRCA, CESC, OV, and UCEC.
ND—Not determined due to model non-convergence
*BLCA omitted due to only n = 2 cancers diagnosed at Stage I
**Relative risk calculated utilizing the cutpoint determined using maximally selected rank statistics

TABLE 3B
Relative risk for diagnosis with stage 3 or 4 disease, relative to stage 1 or
2, according to mutational signatures related to disease-specific survival.

					Maxstat
			Continuous	Discrete	Relative
Cancer*	Signature	Signature Description	(p-value**)	(p-value**)	Risk***	Lower CI	Upper CI

BRCA	SBS12	Liver-cancer related	0.0325	0.61	1.3438	1.0396	1.7368
	SBS22	Aristolochic acid	0.0213	0.14	0.6237	0.4321	0.9004
CESC	_all—	Stage missing
COAD	SBS1	Endogenous clock-like age	0.016	0.0155	0.6250	0.4866	0.8026
	SBS6	Mismatch Repair	0.0055	0.0075	0.6076	0.4438	0.8318
	SBS14	Mismatchrepair + PolEpsilon	0.0063	0.0021	0.4786	0.2924	0.7836
	SBS15	Mismatch repair	0.0034	0.0185	0.4181	0.237	0.7376
	SBS20	Mismatchrepair + POLD1mut	0.0021	0.0041	0.6123	0.4247	0.8826
	SBS33	Unknown	0.0012	0.0018	0.7148	0.5332	0.9583
	SBS39	Unknown	0.2244	0.9573	1.3751	1.038	1.8218
HNSC	SBS2	Endogenous Apobec3a	0.1445	0.3949	1.1640	1.0163	1.3332
	SBS4	Tobacco	0.1959	0.732	1.1444	1.0195	1.2845
	SBS24	Aflatoxin	0.2453	0.375	1.1306	1.0242	1.248
	SBS29	Tobacco	0.1974	0.2593	1.1500	1.0409	1.2705
	SBS31	PLChemotherapy	0.2613	0.5023	1.1273	1.0007	1.2699
LGG	_all—	Stage missing
LIHC	SBS24	Aflatoxin	0.0715	0.0474	1.7451	1.122	2.714
	SBS25	Chemotherapy	0.7238	0.793	1.5335	1.0309	2.2814
	SBS84	Actind cytidine deaminase	0.0088	0.2167	1.7365	1.1284	2.6724
LUAD	SBS25	Chemotherapy	0.3480	0.437	1.5546	1.0058	2.4030
	SBS29	Tobacco	0.0068	0.0882	1.5384	1.0089	2.3458
LUSC	SBS1	Endogenous clock-like age	0.2526	0.5205	3.9657	1.0116	15.5467
	SBS23	Unknown	0.3356	0.5686	2.2129	1.3928	3.5159
	SBS25	Chemotherapy	0.0411	0.0949	1.6952	1.0646	2.6992
OV	_all—	Stage missing
PAAD	SBS32	AZA Chemotherapy	0.1111	0.8842	4.2668	1.2007	15.163
SARC	_all—	Stage missing
SKCM	SBS4	Tobacco	0.0039	0.9926	1.6503	1.271	2.1429
	SBS7c	Ultraviolet	0.3486	0.8503	0.7935	0.6377	0.9874
	SBS10b	Polymerase epsilon	0.7141	0.6232	0.8091	0.656	0.998
		mutation
	SBS36	Base excision repair MUTY	0.3444	0.9259	1.5259	1.0355	2.2485
	SBS38	Ultraviolet	0.0334	0.0264	0.5749	0.3437	0.9618
STAD	SBS1	Endogenous clock-like age	0.0106	0.7954	0.8651	0.6997	1.0697
	SBS7c	Ultraviolet	0.0154	0.7877	1.2383	0.9872	1.5531
	SBS16	Unknown	0.0308	0.6479	0.6958	0.4827	1.0000
	SBS19	Unknown	0.0072	0.1246	1.0700	0.8730	1.3115
	SBS20	Mismatchrepair + POLD1mut	0.0845	0.0143	0.8688	0.6594	1.1447
	SBS26	Mismatchrepair	0.0303	0.6375	0.8767	0.6264	1.2190
	SBS29	Tobacco	0.0500	0.1886	0.9649	0.7883	1.1810
	SBS34	Unknown	0.0089	0.7431	1.1945	0.9546	1.4946
	SBS39	Unknown	0.0280	0.4674	1.1622	0.9439	1.4309
UCEC	_all—	Stage missing
Included are those signatures deemed significant at p-value < false discovery rate threshold
All relationships adjusted for age and sex.
*BLCA omitted due to only n = 2 cancers diagnosed at Stage I
**p-values for trend in unit of mutational signature in relation to stage 3 and 4 combined, vs. stage 1 and 2 combined
***Relative risk calculated utilizing the cutpoint determined using maximally selected rank statistics

Contribution of Mutational Signatures and TMB to DSS

The concordance index (c-index) calculated for a Cox proportional hazards model for DSS that included age at diagnosis, sex and tumor stage (baseline model), was compared to that calculated for models that also included mutational signatures, and recalculated again with addition of tumor mutational burden (TMB). For included tumors, mutational signatures added significantly to the c-index, indicating that the signatures contributed to prediction of DSS, except for 3 cancers in which no signatures met the false discovery rate (FDR) requirement (Table 4). For 10 cancers, TMB had also contributed to survival discrimination in the baseline model analysis (exceptions were CESC, HNSC, LGG, LUSC, PAAD, and SARC). When TMB was then added to models that incorporated clinical factors and signatures, TMB did not add further prognostic discrimination, as measured by the c-index. For many cancers, the final c-index exceeded that attained in published clinical models that included many factors not available in TCGA, suggesting that inclusiont of those clinical factors alone will not account for the higher discrimination of mutational signatures in DSS.

TABLE 4
Survival models including clinical factors only, and effect of addition of mutational signatures
and tumor mutational burden (TMB), as measured by the concordance Index (c-index).

					Likelihood
				Model	Ratio p-
				Concordance	value -	Model	Likelihood	TMB
		Concordance		Clinical	Addition	Concordance	Ratio p-	association
		Clinical	Signatures (p <	Factors	of	Clinical +	value -	with DSS
	Clinical	Factors	False Discovery	(col B) +	Signatures	Signatures	Addition	(adjusted
	Factors	(col B)	Rate (FDR)	Signatures	(Model	(col E) +	of TMB	for clinical
Cancers	available:	only	Threshold)	(col D)	col E)	TMB	(col G)	only)

BLCA	Stage{circumflex over ( )}, Age,	0.64	SBS1, 2, 7a, 10b,	0.76	<.0001	0.76	0.92	p < .05
	Sex, Grade		13, 22, 23, 39
	Stage, Age,
BRCA	Sex	0.76	SBS10b, 12, 20, 22, 30	0.8	0.0001	0.8	0.06	p < .05
CESC	Age, Grade	0.57	SBS7a, 34, 42	0.67	<.0001	0.67	0.63	No
	Stage, Age,
COAD	Sex	0.75	SBS9, 17b, 25, 26, 36	0.84	<.0001	0.84	0.6	p < .05
	Stage, Age,
HNSC	Sex, Grade	0.58	SBS9, 85	0.59	0.004	0.6	0.08	p < .05
	Age, Sex, Grade
LGG	Stage, Age,	0.79	SBS1, 8, 12, 25	0.83	<.0001	0.83	0.14	No
LIHC	Sex, Grade	0.72	SBS1, 4, 6, 7a, 7c, 15,	0.8	<.0001	0.8	0.12	p < .05
			19, 21, 24, 39, 85
LUAD			No p < FDR					p < .05
LUSC			No p < FDR					No
OV	Age, Grade	0.61	SBS7a, 39	0.63	<.0001	0.63	0.22	p < .05
	Stage, Age,
PAAD	Sex, Grade	0.60	SBS8, 44	0.65	<.0001	0.65	0.37	No
SARC	Age, Sex		No p < FDR					No
	Stage, Age,		SBS1, 4, 7a, 7b, 7c,
			7d, 10b, 13, 17a, 25,
SKCM	Sex	0.56	31, 34, 39	0.67	<.0001	0.67	0.887	p < .05
	Stage, Age,
STAD	Sex, Grade	0.64	SBS10b	0.67	0.0003	0.67	0.37	p < .05
UCEC	Age, Grade	0.71	SBS1, 6, 10a, 10b, 13,	0.84	<.0001	0.84	0.29	p < .05
			14, 15, 16, 17a, 17b,
			18, 20, 22, 26, 29, 33,
			34, 38, 39

Signatures included if p-value<false discovery threshold

Abbreviations

• • FDR—False Discovery Rate
  • TMB—Tumor Mutational Burden

TABLE 5
Modification of the effect of radiotherapy on
cancer survival by mutational signatures, among
those with Stage II or later disease.

Signature
Present	NonEvents	Events	Hazard		p-value

Yes	Rad	n	n	Ratio	95% CI	interaction

SBS7c:

.045

Yes	Yes	15	7	1.20	0.53-2.72
No	Yes	597	148	0.78	0.60-1.00
Yes	No	128	40	0.61	0.41-0.90

SBS24

.031

Yes	Yes	183	66	1.11	0.78-1.58
No	Yes	429	89	0.70	0.52-0.95
Yes	No	618	240	1.07	0.85-1.36

SBS29

.0038

Yes	Yes	66	32	1.43	0.92-2.21
No	Yes	546	123	0.70	0.53-0.93
Yes	No	275	86	0.88	0.63-1.22

SBS37

.05

Yes	Yes	52	8	0.44	0.16-1.18
No	Yes	560	147	0.87	0.67-1.12
Yes	No	164	69	1.27	0.92-1.76

SBS42

.028

Yes	Yes	75	23	1.30	0.77-2.19
No	Yes	537	132	0.76	0.58-0.99
Yes	No	264	111	1.00	0.76-1.31

Adjusted for age, gender, type of cancer, and immortal person-time. Also restricted to TCGA participants who lived 365 days or longer, and to Stage 2 pathologic stage or later.

The joint effects of five signatures (SBS7c, SBS24, SBS29, SBS37, SBS42) and radiotherapy differed from that expected on a multiplicative scale. In patients with four signatures (SBS7c, SBS24, SBS29, SBS42), radiotherapy did not decrease risk of mortality. In patients with signature SBS37, radiotherapy decreased risk of mortality more than expected. These results suggest that the presence of particular signatures in the genetic background of the tumor may be predictive, that is, influence response to therapy, as well as prognostic, providing information about overall survival.

Discussion

The understanding of contributions to cancer survival by specific mutagen exposure and unrepaired damage to DNA is minimal. Mutational signatures have not previously been comprehensively evaluated in relationship to clinical outcomes (stage, survival), thus the present findings provide evidence for clinical utility for such signatures. The findings suggest that signatures that are risk factors for incidence, such as mismatch repair, will not necessarily act similarly in the survival setting, and may differ in relation to disease-specific survival in important ways. Mutational signatures of carcinogen damage, and of endogenous processes such as DNA repair, were strongly associated with cancer survival. Such damage, and lack of repair, points to underlying cellular events that may drive tumor growth and proliferation, lack of responsiveness to cell cycle/apoptotic signals, and other mechanisms associated with poor prognosis. The results also indicate that tumor mutational burden may be decomposed into constituents that more strongly predict survival than the overall TMB measure. Signatures not previously linked to survival outcomes may suggest new pathogenic mechanisms. Taken together, the findings open new prospects on the understanding of survival determinants and may eventually present opportunities to provide more precisely-tailored care.

Often, risk factors for survival differ from those for incident cancer. In addition, as the same risk factor can be associated with increased risk of one cancer but reduced risk of another, it was unlikely for that to differ in the survival context. Thus, it was not unexpected that mutational signatures associated with disease incidence would have disparate relationships to disease-specific survival, in identity, magnitude, or direction. DNA repair and UV exposure are notable examples in this study: individuals with greater UV exposure have an increased melanoma incidence in the literature¹⁹, but decreased melanoma mortality in this study as well as others (Berwick et al., 2005; Heenan et al., 1991; Rosso et al., 2008). Cancer DSS is likely to involve mechanisms directly facilitating metastasis, including intravasation of blood vessels and establishment of a metastatic niche at a distant organ site, which are clearly distinct from cancer incidence processes (Valastyan & Weinberg, 2011). Thus, as metastasis is the most common cause of disease-specific mortality, endogenous and exogenous mutational processes involved in cancer initiation are expected to act somewhat differently to influence survival.

While endogenous signatures such as those of clock-like aging and APOBEC have only rarely been investigated in association with DSS (Chen et al., 2017), the prognosis associated with endogenous DNA repair defects has been more extensively studied. Deficiencies in DNA repair, such as those in mismatch and homologous repair, inherited as mutations in genes such as MLH1, PMS2, and BRCA1/2, cluster in families and predispose to increased cancer incidence. However, their relationship with cancer survival is more complex. In a number of studies, patients with Lynch Syndrome I/II, associated with inherited mismatch repair (MMR) mutations, have had improved cancer prognosis (Gryfe et al., 2000), possibly due to enhanced response to therapy (Sinicrope et al., 2011). Lack of MMR and concomitant reduced DNA repair may lead to increased cancer cell death in chemotherapy treatment, facilitating increased survival. Mismatch repair deficiencies also favor improved survival in immune checkpoint inhibitor therapy (Le et al., 2015). In contrast, BRCA 1/2 patients, whose mutations confer homologous repair deficiencies, have had similar cancer survival as unaffected individuals in many (Goodwin et al., 2012; Lee et al., 1999; Verhoog et al., 1999; Verhoog et al., 1998; Copson et al., 2018) but not all (Castro et al., 2013; Schmidt et al., 2017) studies. The present results suggest that signatures of increased MMR (some of which may be due to inherited genetic alterations, some somatically acquired) are not uniformly associated with prognosis. In LIHC and STAD, individuals with MMR signatures have a reduced risk of disease-specific mortality, relative to unaffected individuals. In other tumors (BRCA, COAD), MMR deficiency signatures are associated with increased mortality. Lack of information on treatment, specifically chemotherapy, does not allow stratification to further explore mechanistic understanding. The present findings also suggest that COAD and LGG patients with a base excision repair deficiency signature have increased disease-specific mortality. As inheritance of contributing factors is rare; it is likely that most endogenous signatures above were somatically acquired.

Effects of signatures of exogenous mutagens in many cases mirror those from human studies of carcinogen exposure, lending validity to prognostic risk factor findings, and vice-versa. As one illustration, UV light exposure has been associated with decreased risk of bladder cancer incidence (Lin et al., 2012) and mortality (Chen et al., 2010a) as well as reduced cervical cancer mortality (Chen et al., 2010a). Individuals with greater exposure to UV light have an increased incidence of melanoma (Lin et al., 2012) but often have reduced melanoma mortality (Berwicke t al., 2005; Heenan et al., 1991; Rosso et al., 2008), although evidence from ecological studies has been less consistent (Garland et al., 2003; Lachiewicz et al., 2008; Jemal et al., 2000). The three signatures of UV related to melanoma mortality in this study (SBS7a, 7b, 7c) were each associated with diminished risk. Enhanced Vitamin D serum levels have been implicated as a mechanism in the reduced mortality (Newton-Bishop et al., 2009; Hardie et al., 2020). For LIHC, however, patients bearing either of two signatures of UV-related DNA damage in tumors (SBS7a, SBS38) had an elevated mortality risk, which has not been identified in the literature. Individuals carrying tobacco-related DNA-damage signatures (Hollstein et al., 2017) in tumors had an increased mortality risk in BRCA, LGG, and SKCM, each with some support from findings from prognostic risk factor studies (Hardie et al., 2020; Abdel-Rahman & Cheung, 2018; Passarelli et al., 2016; Hou et al., 2016; McLaughlin et al., 1995; Newton-Bishop et al., 2015). While smoking both has (Hardie et al., 2020; Newton-Bishop et al., 2015) and has not (DeLancey et al., 2011; Givson et al., 2020) been related to increased melanoma mortality, in this study individuals with smoking-associated signatures were diagnosed with later melanoma stage, and a discrete measure of smoking-related damage exhibited a significant trend with DSS. The tobacco-related associations noted in this study omit a few previously reported in the literature, including those excluded due to failure to exceed the FDR threshold. Aristolochic acid, an herbal medicine additive (Poon et al., 2013), has been implicated in urinary tract but not specifically bladder cancer prognosis (Wang et al., 2019). An initial relationship with bladder cancer, however, may have come to light due to mutational signatures (Poon et al., 2015), illustrating the potential richness of reciprocal exchanges between mutational signature findings and risk factor investigations. Among other exogenous mutagen relationships identified, aflatoxin has been associated with liver (Chen et al., 2013) and non-liver cancer mortality (Hayes et al., 1984), while chemotherapy signatures indicate an earlier, advanced stage primary tumor, which has an established relationship with prognosis (Wang et al., 2020; Jegu et al., 2015).

While the findings of increased DSS in some tumors but reduced in others for the same carcinogen or signature may initially seem at odds, it is important to note that UV and smoking, for example, have similar relationships with disease incidence: UV exposure appears to reduce risk of many tumors (Lin et al., 2012; Boscoe & Schymura, 2006), but not melanoma (Lin et al., 2012), and smoking has been associated with reduced incidence of both endometrial cancer (Lindemann et al., 2008; Brinton et al., 1993) and Parkinson's disease (Checkoway et al., 2002; Chen et al., 2010b). Thus, opposing directions of signature-mortality relationships by cancer is not unexpected, but requires further validation. In all instances cited above, the associations identified in the literature are weaker than those in this study, suggesting that cutpoints identified by maximally selected rank statistics will possibly be subject to “regression to the mean”-like declines with further investigation, or that self-report of smoking, UV, or other carcinogenic exposures are subject to non-differential misclassification and other measurement error, or both. Signatures detected in this study are also those not repaired by physiologic mechanisms, implying a role for DNA repair and for threshold effects. In sum, these findings suggest that biologically-based measures of carcinogen exposure in tumors, when fully validated, will augment and clarify relationships in the literature, as well as provide hypotheses for investigation.

Individuals with high tumor mutational burden (TMB) have had a mixed prognosis in previous studies, often tumor type- and treatment-dependent (Shao et al., 2020; Samstein et al., 2019; Rivierre et al., 2020). Higher TMB is associated with improved overall survival in those who received immune checkpoint inhibitors (ICI) (Altan et al., 2017) therapy, which received FDA approval after recruitment for TCGA. Defects in DNA mismatch repair in particular have been correlated with TMB (Chalmers et al., 2017). In at least one analysis, TMB has been only weakly associated with survival after inclusion of other contributing factors, including mutations in DNA repair genes (Aoude et al., 2020). SBS signatures may serve, in part, as a surrogate but potentially stronger measure of TMB because they are a summary measure of pathogenic mutations, gene methylation, and other potentially contributing events (Chen et al., 2017; Chalmers et al., 2017; Aoude et al., 2020; Chen et al., 2020c). The present analysis suggests that the relationship between individual signatures and DSS varies uniquely for each tumor, however, thus it is unlikely that TMB is the underlying foundation of all relationships between signatures and DSS. The present multivariable analysis results also indicate that SBS signatures are contributing to cancer survival independently of TMB, while TMB is rarely contributing to DSS independently of signatures, setting the stage for further investigation of their distinct role.

Signatures of many carcinogens have not been identified, and conversely, the etiology of many recognized mutational signatures is as yet unclear. Thus, 24 of 80 signatures (30%) related strongly to DSS are of unknown origin. In addition, despite restricting cancers to those with >50 events and cutpoints to cell sizes>5, some signatures are based on small cells, and may be false positive findings. Analyses of continuous, discrete, and stage-specific measures were conducted in part to provide a broader basis for evaluation of these findings. The FDR was also utilized, and reported findings limited to only those that exceeded the FDR threshold. The large sample sizes overall, follow-up for several years, and availability of numerous signatures with potential prognostic utility are among the study strengths.

Mutational signatures contain substantial promise for enhancing mechanistic understanding, outcome discrimination, and for confirmation of prognostic risk factor findings, as well as for generation of novel hypotheses. SBS signatures require validation in tumor sequencing studies before undergoing further consideration for clinical use.

Abbreviations

• • ACC Adrenocortical carcinoma
  • BLCA Bladder Urothelial Carcinoma
  • LGG Brain Lower Grade Glioma
  • BRCA Breast invasive carcinoma
  • CESC Cervical squamous cell carcinoma and
  • endocervical adenocarcinoma
  • CHOL Cholangiocarcinoma
  • COAD Colon adenocarcinoma
  • ESCA Esophageal carcinoma
  • GBM Glioblastoma multiforme
  • HNSC Head and Neck squamous cell carcinoma
  • KICH Kidney Chromophobe
  • KIRC Kidney renal clear cell carcinoma
  • KIRP Kidney renal papillary cell carcinoma
  • LIHC Liver hepatocellular carcinoma
  • LUAD Lung adenocarcinoma
  • LUSC Lung squamous cell carcinoma
  • DLBC Lymphoid Neoplasm Diffuse Large B-cell b
  • Lymphoma
  • MESO Mesothelioma
  • OV Ovarian serous cystadenocarcinoma
  • PAAD Pancreatic adenocarcinoma
  • PCPG Pheochromocytoma and Paraganglioma
  • PRAD Prostate adenocarcinoma
  • READ Rectum adenocarcinoma
  • SARC Sarcoma
  • SKCM Skin Cutaneous Melanoma
  • STAD Stomach adenocarcinoma
  • TGCT Testicular Germ Cell Tumors
  • THYM Thymoma
  • THCA Thyroid carcinoma
  • UCS Uterine Carcinosarcoma
  • UCEC Uterine Corpus Endometrial Carcinoma

Signature Definitions

• • SBS1=Endogenous clock-like age
  • SBS2=Endogenous Apobec3a
  • SBS3=Homologous repair
  • SBS4=Tobacco
  • SBS5=Endogenous clock-like age
  • SBS6=Mismatchrepair
  • SBS7a=UV
  • SBS7b=UV
  • SBS7c=UV
  • SBS7d=UV
  • SBS8=Unknown
  • SBS9=PolETA Somatichypermutation
  • SBS10a=Polymerase epsilon hypermutations
  • SBS10b=Polymerase epsilon mutations
  • SBS11=Temozolo Chemotherapy
  • SBS12=Liver cancer
  • SBS13=Endogenous apobec
  • SBS14=Mismatchrepair+PolEpsil
  • SBS15=Mismatchrepair
  • SBS16=Unknown
  • SBS17a=Unknown
  • SBS17b=Unknown
  • SBS18=ReactiveOxy
  • SBS19=Unknown
  • SBS20=Mismatchrepair+POLD1mut
  • SBS21=Mismatchrepair
  • SBS22=Aristolochic acid
  • SBS23=Unknown
  • SBS24=Aflatoxin
  • SBS25=Chemotherapy
  • SBS26=Mismatchrepair
  • SBS28=Unknown
  • SBS29=Tobacco chewing in Hollstein
  • SBS30=BER repair-NTHL1 mut
  • SBS31=PLChemotherapy
  • SBS32=AZA Chemotherapy
  • SBS33=Unknown
  • SBS34=Unknown
  • SBS35=PLChemotherapy
  • SBS36=BERrepair MUTY
  • SBS37=Unknown
  • SBS38=UV
  • SBS39=Unknown
  • SBS40=Unknown
  • SBS41=Unknown
  • SBS42=Haloalkane
  • SBS44=Mismatchrepair
  • SBS84=Actind cytidinedeaminase
  • SBS85=Actind cytidinedeaminase
  • SBS86=Chemotherapy

Example 2

It was determined whether single base substitution signatures, covering a range of environmental agent and endogenous exposures, as well as defective DNA repair pathways, were associated with cancer survival. Algorithms for mutational signature assessment were used to elucidate cancer-specific outcomes.

Methods

Tumor exome sequencing data were derived from The Cancer Genome Atlas (TCGA). Description of cancer patient recruitment, follow-up, and ascertainment of disease outcomes has been published. TCGA somatic mutation data of 10,179 patients (reference genome GRCh38) from 33 cancer types were downloaded from the Genomic Data Commons. Eligible cancers were those with at least n=50 disease-specific survival (DSS) events, and only TCGA participants with DSS outcomes that were deemed appropriately defined¹⁰ were retained. Stage 0 cancers were also omitted, and those missing stage were excluded from stage-specific analyses. The probability matrix for 49 established COSMIC reference mutational signatures (v3) was downloaded from Synapse Documentation (https://www.synapse.org/#ISynapse:syn11738319

Signature Identification

The association of mutational signatures with endogenous processes or exogenous mutagens has been described. A catalog of 96 three-nucleotide motifs that surround the mutational focus (one upstream nucleotide+mutation site+one downstream nucleotide site) was prepared, and frequency tables of this motif catalog derived for each involved patient. A computational function from R package MutationalPatterns was used to fit the patient mutational motif frequency tables to the reference mutational signatures while requiring the coefficients, i.e., signature-to-patient contribution strengths, be non-negative values. The estimated coefficients came out in the form of a 96-by-10,179 matrix of non-negative values.

Statistical Analysis

Disease-specific survival (DSS) was the outcome of interest. Thus, disease-specific mortality was counted as an event, and deaths from other causes (competing risks) and loss-to-follow up were censored. Time to event (cancer, other cause of death, or end of follow-up period) was calculated by TCGA as days from cancer diagnosis. To correct for disease-free immortal person-time, which is present in the time from diagnosis to recruitment, disease-specific survival time was re-calculated. As the exact surgery dates of TCGA patients are unknown, a three-month interval was assumed for patients to sustain from initial diagnosis to the recruitment date and such a three-month-period was subtracted from each patient's disease-free survival. Mutational signatures were modeled in relationship to survival as continuous or discrete (excluding zero) measures, and also using a single cutpoint determined by maximally selected rank statistics, employing a restriction that the cutpoint include cell sizes of 5 or greater. The three clinical factors commonly available for all organ sites in TCGA data, age at diagnosis, sex, and stage, were included in all analyses. Cox proportional hazards models for DSS, estimating hazard ratios (HR) and 95% confidence intervals (CI), were fit. The proportional hazards assumption was verified by Schoenfeld residuals. Correction for immortal person-time was included, and all events that occurred prior to study consent excluded. To further establish the nature of the relationship between mutational signatures and DSS, it was also determined whether stage at diagnosis differed according to signature, comparing Stage I to Stage III/IV disease, using the measures and adjustment factors employed in Cox regression, but quantifying relative risks (RR) and 95% CI.

Models that included only diagnosis age, sex, and disease stage (baseline model) were compared to a model that also included all mutational signatures significantly associated with survival, and also to a third model that incorporated in addition a measure of tumor mutational burden (TMB). Then a concordance statistic (c-statistic, commonly known as c-index) was calculated to compare improvement in model fit with sequential incorporation of these measures. The difference in c-index between the baseline and other models was assessed. Tumor mutational burden was quantified to evaluate nonsynonomous somatic mutations (references here), and included as a continuous variable. A two-tailed p-value of <0.05, after adjustment for the false discovery rate (FDR) of 0.10, was considered significant.

Results

Of solid tumors, 14 organ sites, constituting 15 distinct pathological entities or cancer types, and 6292 patients were included in the analysis, after exclusion of those with less than 50 DSS events (Supplementary Table 1). Included cancer types ranged from n=163 for pancreatic adenocarcinoma (PAAD) to n=917 for breast carcinoma (BRCA)) (Table 1; see above). Mean age of included patients ranged from 43.2 years [Low Grade Glioma (LGG)] to 68.0 [Bladder Carcinosarcoma (BLCA)]. Signatures of 49 distinct mutational patterns of single base substitution (SBS) were examined in relationship to DSS¹².

Signatures Associated with Stage III/IV Disease

Among the nine cancers with stage information, all had signatures associated with later stage (III/IV) vs earlier (I/II), either as continuous or discrete measures, or using a single cutpoint (Table 2; see above). Risk of later stage disease was generally lower among those with the mismatch repair and ultraviolet exposure signatures. Later stage disease was more common among those with signatures of tobacco exposure and previous chemotherapy.

Signatures Associated with DSS

The number of signatures related to altered survival per tumor, after consideration of FDR ranged from none {(Lung adenocarcinoma (LUAD) Lung squamous cell (LUSC), and Sarcoma (SARC)} to 13 [Skin Cutaneous Melanoma (SKCM, Table 2)]. While results derived using continuous or discrete measures often supported those obtained using other means, only those relationships identified using a single cutpoint and evaluated using hazard ratios are described below.

Among endogenous mutation measures (FIGS. 1 and 2), the most common etiology of the mutational signatures identified was a clock-like signature associated with aging (SBS1), implicated in survival of 6 cancers, including Colon Adenocarcinoma (COAD), LGG, Liver hepatocellular carcinoma (LIHC), Ovarian Serous Cystadenocarcinoma (OV), Stomach Adenocarcinoma (STAD), and Uterine Corpus Endometrial Carcinoma (UCEC) (FIG. 1). The effect of the aging signature on survival was mixed, in that risk of cancer-specific mortality was reduced among participants with BLCA, and UCEC cancers (HR=0.50, HR=0.30, respectively), but elevated up to 3.65-fold in other cancers. Two signatures (SBS2 and SBS13) of deregulated APOBEC-related cytosine deamination activity were both associated with reduced mortality in BLCA patients (HR=0.44, HR=0.46, respectively), but in BRCA, risk of disease-specific mortality was elevated, using continuous or discrete measures. Defects in DNA repair mechanisms that may have contributed to altered survival include several signatures of mismatch repair (SBS14, 20, 26) in BRCA, COAD, and UCEC tumors, in which BRCA and COAD patients had up to 3.2-fold increased mortality risk, but mortality in UCEC was substantially reduced (HR=0.13). A base excision repair signature (SBS30) was related to 1.5, 1.74, and 2.6 fold increased mortality, respectively, in BLCA, LGG, and BRCA. Polymerase epsilon, which acts in both replication and DNA recombination, also facilitates completion of base excision and nucleotide excision repair, thus signatures of defective polymerase epsilon (SBS10a, SBS10b) in BLCA, BRCA, SKCM, or STAD survival could be attributed to these several cellular mechanisms. In addition to the above, a further endogenous process implicated in DSS is activation-induced cytidine deaminase in 3.5 and 5-fold increased risks of disease-specific mortality in LIHC and Head and Neck Squamous Cell Carcinoma (HNSC).

Among signatures of exogenous mutagenic agents (FIGS. 3 and 4), that associated with aristolochic acid, an herbal medicine component (SBS22), was related to reduced mortality in BLCA (HR=0.33) (Table 2). Ultraviolet (UV) exposure, as captured by the SBS7a, 7b, 7c signatures, was related to reduced mortality in BLCA, OV and SKCM cancers (HR=0.35-0.56; Table 2). Those with signatures of tobacco exposure¹⁷ (SBS4, SBS29) had increased risks of cancer mortality in BRCA (4-fold), LGG (2.2 to 2.8-fold), and SKCM (3-fold). COAD, LGG, LUSC, and SKCM patients bearing a signature of previous chemotherapy treatment (SBS11, SBS25, SBS31) had 4 to 5-fold elevated risks of mortality due to their respective cancers, while chemotherapy-related mortality was elevated 2.5-fold in BLCA. CESC and COAD-specific mortality were increased 3-8-fold among those whose cancers demonstrated the mutational signatures of haloalkanes (SBS42), an organic solvent exposure incurred occupationally¹⁸. Aflatoxin mutagenesis (SBS24) was associated with a 3-fold increased risk of LGG-specific mortality and a greater than 13-fold increased risk of mortality among those with LIHC. Among COAD patients, those with a signature of reactive oxygen species (SBS18), considered a metabolite of carcinogenic exposures but also generated endogenously, had a 3.5-fold increased risk of disease-specific mortality.

To evaluate one possible mechanism whereby mutational signatures might influence survival, we assessed the relationship between signature and stage within each cancer. Of the n=46 evaluable relationships, 10 were also associated with stage at diagnosis when assessed using continuous, discrete, or the binary survival cutpoint measures. However, many with strong relationships with DSS (continuous or discrete, and binary cutoff) were not associated with stage at diagnosis (COAD and SBS26 (mismatch repair), LIHC and SBS1 (Endogenous clock-like age), SKCM and SBS7b (UV), and SKCM and SBS10b (Polymerase Epsilon) are among those).

Contribution of Mutational Signatures and TMB to DSS

The concordance index (c-index) calculated for a Cox proportional hazards model for DSS that included age at diagnosis, sex and tumor stage (baseline model) was compared to that calculated for models that also included mutational signatures, and recalculated again with the addition of tumor mutational burden (TMB). For all 15 included tumors, mutational signatures added additional prognostic discrimination to the c-index, indicating that the signatures contributed to prediction of DSS (Table 4). For 9 cancers, TMB had also contributed to survival discrimination in the baseline model analysis (exceptions were CESC, HNSC, LGG, LUSC, PAAD, and SARC). When added to models that incorporated clinical factors and signatures, TMB did not add further prognostic discrimination, as measured by the c-index (Table 4) For many cancers, the final c-index exceeded that attained in clinical models that included many factors not available in TCGA, suggesting that inclusion of those clinical factors alone will not account for the higher discrimination of DSS.

Discussion

An understanding of contributions to cancer survival by specific mutagen exposure and unrepaired damage to DNA is minimal. Mutational signatures have not previously been comprehensively evaluated in relationship to clinical outcomes (stage, survival), thus our findings provide evidence for clinical utility for such signatures. The findings suggest that signatures that are risk factors for incidence, such as mismatch repair, will not necessarily act similarly in the survival setting, and may differ in relation to disease-specific survival in important ways. It was found that mutational signatures of carcinogen damage, and of endogenous processes such as DNA repair, were strongly associated with cancer survival. Such damage, and lack of repair, points to underlying cellular events that may drive tumor growth and proliferation, lack of responsiveness to cell cycle/apoptotic signals, and other mechanisms associated with poor prognosis. The results also indicate that tumor mutational burden may be decomposed into constituents that more strongly predict survival than the overall TMB measure. Signatures not previously linked to survival outcomes may suggest new pathogenic mechanisms. Taken together, the findings open new prospects on our understanding of survival determinants and may eventually present opportunities to provide more precisely-tailored care.

Often, risk factors for survival differ from those for incident cancer. In addition, as the same risk factor can be associated with increased risk of one cancer but reduced risk of another, it was unlikely for that to differ in the survival context. Thus, it was not unexpected that mutational signatures associated with disease incidence would have disparate relationships to disease-specific survival, in identity, magnitude, or direction. DNA repair and UV exposure are notable examples in this study: individuals with greater UV exposure have an increased melanoma incidence in the literature, but decreased melanoma mortality in this study as well as others. Cancer DSS is likely to involve mechanisms directly facilitating metastasis, including intravasation of blood vessels and establishment of a metastatic niche at a distant organ site, which are clearly distinct from cancer incidence processes. Thus, as metastasis is the most common cause of disease-specific mortality, endogenous and exogenous mutational processes involved in cancer initiation are expected to act somewhat differently to influence survival.

While endogenous signatures such as those of clock-like aging and APOBEC have only rarely been investigated in association with DSS, the prognosis associated with endogenous DNA repair defects has been more extensively studied. Deficiencies in DNA repair, such as those in mismatch and homologous repair, inherited as mutations in genes such as MLH1, PMS2, and BRCA1/2, cluster in families and predispose to increased cancer incidence. However, their relationship with cancer survival is more complex. In a number of studies, patients with Lynch Syndrome I/II, associated with inherited mismatch repair (MMR) mutations, have had improved cancer prognosis, possibly due to enhanced response to therapy. Lack of MMR and concomitant reduced DNA repair may lead to increased cancer cell death in chemotherapy treatment, facilitating increased survival. Mismatch repair deficiencies also favor improved survival in immune checkpoint inhibitor therapy. In contrast, BRCA 1/2 patients, whose mutations confer homologous repair deficiencies, have had similar cancer survival as unaffected individuals in many but not all studies. The present results suggest that signatures of increased MMR (some of which may be due to inherited genetic alterations, some somatically acquired) are not uniformly associated with prognosis. In LIHC and STAD, individuals with MMR signatures have a reduced risk of disease-specific mortality, relative to unaffected individuals. In other tumors (BRCA, COAD), MMR deficiency signatures are associated with increased mortality. Lack of information on treatment, specifically chemotherapy, does not allow stratification to further explore mechanistic understanding. Our findings also suggest that COAD and LGG patients with a base excision repair deficiency signature have increased disease-specific mortality. As inheritance of contributing factors is rare; it is likely that most endogenous signatures above were somatically acquired.

Effects of signatures of exogenous mutagens in many cases mirror those from human studies of carcinogen exposure, lending validity to prognostic risk factor findings, and vice-versa. As one illustration, UV light exposure has been associated with decreased risk of bladder cancer incidence and mortality as well as reduced cervical cancer mortality. Individuals with greater exposure to UV light have an increased incidence of melanoma but often have reduced melanoma mortality, although evidence from ecological studies has been less consistent. The three signatures of UV related to melanoma mortality in this study (SBS7a, 7b, 7c) were each associated with diminished risk. Enhanced Vitamin D serum levels have been implicated as a mechanism in the reduced mortality. For LIHC, however, patients bearing either of two signatures of UV-related DNA damage in tumors (SBS7a, SBS38) had an elevated mortality risk, which has not been identified in the literature. Individuals carrying tobacco-related DNA-damage signatures in tumors had an increased mortality risk in BRCA, LGG, and SKCM, each with some support from findings from prognostic risk factor studies. While smoking both has and has not been related to increased melanoma mortality, in this study individuals with smoking-associated signatures were diagnosed with later melanoma stage, and a discrete measure of smoking-related damage exhibited a significant trend with DSS. The tobacco-related associations noted in this study omit a few previously reported in the literature, including those excluded due to failure to exceed the FDR threshold. Aristolochic acid, an herbal medicine additive, has been implicated in urinary tract but not specifically bladder cancer prognosis. An initial relationship with bladder cancer, however, may have come to light due to mutational signatures, illustrating the potential richness of reciprocal exchanges between mutational signature findings and risk factor investigations. Among other exogenous mutagen relationships identified, aflatoxin has been associated with liver and non-liver cancer mortality, while chemotherapy signatures indicate an earlier, advanced stage primary tumor, which has an established relationship with prognosis.

While the findings of increased DSS in some tumors but reduced in others for the same carcinogen or signature may initially seem at odds, it is important to note that UV and smoking, for example, have similar relationships with disease incidence: UV exposure appears to reduce risk of many tumors but not melanoma, and smoking has been associated with reduced incidence of both endometrial cancer and Parkinson's disease. Thus, opposing directions of signature-mortality relationships by cancer is not unexpected, but requires further validation. In all instances cited above, the associations identified in the literature are weaker than those in this study, suggesting that cutpoints identified by maximally selected rank statistics will possibly be subject to “regression to the mean”-like declines with further investigation, or that self-report of smoking, UV, or other carcinogenic exposures are subject to non-differential misclassification and other measurement error, or both. Signatures detected in this study are also those not repaired by physiologic mechanisms, implying a role for DNA repair and for threshold effects. In sum, these findings suggest that biologically based measures of carcinogen exposure in tumors, when fully validated, will augment and clarify relationships in the literature, as well as provide novel hypotheses for further investigation.

Individuals with high tumor mutational burden (TMB) have had a mixed prognosis in previous studies, often tumor type- and treatment-dependent. Higher TMB is associated with improved overall survival in those who received immune checkpoint inhibitor (ICI) therapy, which received FDA approval after recruitment for TCGA. Defects in DNA mismatch repair in particular have been correlated with TMB. In at least one analysis, TMB was only weakly associated with survival after inclusion of other contributing factors, including mutations in DNA repair genes. SBS signatures may serve, in part, as a surrogate but potentially stronger measure of TMB because they are a summary measure of pathogenic mutations, gene methylation, and other potentially contributing events. The present analysis suggests that the relationship between individual signatures and DSS varies uniquely for each tumor; however, it is thus unlikely that TMB is the underlying foundation of all relationships between signatures and DSS. The multivariable analysis results also indicate that SBS signatures are contributing to cancer survival independently of TMB, while TMB is rarely contributing to DSS independently of signatures, setting the stage for further investigation of their distinct roles.

Signatures of many carcinogens have not been identified, and conversely, the etiology of many recognized mutational signatures is as yet unclear. Thus, 24 of 80 signatures (30%) related strongly to DSS are of unknown origin. In addition, despite restricting cancers to those with n>50 events and cutpoints to cell sizes≥5, some signatures are based on small cells, and may be false positive findings. We conducted analyses of continuous, discrete, and stage-specific measures in part to provide a broader basis for evaluation of these findings. The FDR was utilized, and limited reported findings to only those that exceeded the FDR threshold. The large sample sizes overall, follow-up for several years, and availability of numerous signatures with potential prognostic utility are among the study strengths. Mutational signatures contain considerable promise for enhancing mechanistic understanding, for outcome discrimination, and for confirmation of prognostic risk factor findings, as well as for generation of novel hypotheses.

Example 3

Exemplary Uses of Signatures in Clinical Medicine

Example A. Keytruda (generic name Pembrolizumab) is a monoclonal antibody that blocks the PD-1/PD-L1 pathway, and is FDA-approved for treatment in children or adults with unresectable or metastatic solid tumors (with the exception of central nervous system), that have progressed following treatment, and that have no satisfactory therapy options. For patients in that context, an additional requirement for therapy eligibility is tumor mutational burden (TMB), as determined by the FDA-approved test F1CDx. In the study described in Example 1, the mutational signatures for all 16 solid tumors exceed TMB in prediction of disease-specific survival (DSS) using the concordance index, regardless of whether TMB is measured on a continuous scale or modeled as a dichotomous variable. Thus, specific signatures for each cancer, or several in combination, may be more useful to determine treatment eligibility for Keytruda than the existing FDA-approved TMB test.

Tumor mutational burden is currently tested using the F1CDx™ assay from Foundation Medicine or via next-generation sequencing panels from select commercial reference laboratories. FDA-approved assessment for TMB may be readily adaptable to assessment for the mutational signatures disclosed herein. Patients with higher TMB have had a more favorable response to PD1/PD-L1 blockade in numerous cancers in the literature (Goodman 2017, McGrail 2021) thus the mutational signatures identified herein may allow additional FDA-approved indications for Keytruda. The mutational signatures in this invention may be particularly relevant to Keytruda use in Melanoma, one of the cancers include in this invention. Melanoma is an example where the deconvolution of TMB into component mutational signatures may refine and hone therapy benefit, as the signatures related to reduced mortality risk might or might not be useful to define individuals who may not benefit from Immune checkpoint therapy. Thus, use of mutational signatures may be particularly useful in determining benefit from Keytruda in brain tumors, bladder cancers and head and neck cancers.

Example B. In several studies, TMB is a predictor of response to not only Keytruda, but also Opdivo (Nivolumab) in non-small cell lung cancer (NSCLC). In the study in Example 1, mutational signatures did not pass a threshold for false discovery rate for subsets of lung cancer (LUAD and LUSC) that make up NSCLC. However, statistical power was restricted due to the use of subsets by TCGA, and mutational signatures disclosed herein may be useful to determine benefit from these therapies in individuals with NSCLC.

Example C. The immune checkpoint inhibitors cemiplimab, atezolimab, avelumab, and durvalumab are not currently approved for use in conjunction with a TMB assay but by their mechanism, may very well prove to be most beneficial in those with high TMB. Thus, the use of the signatures disclosed herein may well help determine clinical benefit with these treatments as well.

Example 4

Individuals carrying tobacco-related DNA-damage signatures (Hollstein et al., 2017) in tumors had an increased mortality risk in breast (BRCA), low grade glioma (LGG), and melanoma (SKCM), each with some support from findings from prognostic risk factor studies (Hardie et al., 2020; Abdel-Rahman & Cheung, 2018; Passarelli et al., 2018; Hou et al., 2016; McLaughlin et al., 1995; Newton-Bishop et al., 2015). While smoking both has (Hardie et al., 2020; Newton-Bishop et al., 2015) and has not (DeLancey et al., 2011; Gibson et al., 2020) been related to increased melanoma mortality, in this study individuals with smoking-associated signatures were diagnosed with later melanoma stage. Tobacco-related signatures were not associated with risk of disease-specific survival in the two lung cancer subgroups included (Lung adenocarcinoma and lung squamous cell carcinoma).

Individuals with greater exposure to UV light have an increased incidence of melanoma (Lin et al., 2012) but often have reduced melanoma mortality (Berwick et al., et al., 2005; Heenan et al., 1991), although evidence from ecological studies has been less consistent (Garland et al., 2003; Lachiewicz et al., 2008; Jemal et al., 2000). We found reduced melanoma mortality in association with several UV signatures but not all in our study.

Mismatch repair (MMR) deficiency is generally associated with increased risk of cancer incidence but reduced risk of mortality, in part due to improved response to chemotherapy. Our results suggest that signatures of increased MMR (some of which may be due to inherited genetic alterations, some somatically acquired) are not uniformly associated with improved prognosis. In LIHC and STAD, individuals with MMR signatures have a reduced risk of disease-specific mortality, relative to unaffected individuals. In other tumors (breast (BRCA), colon (COAD)), MMR deficiency signatures are associated with increased mortality.

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All publications, patents and patent applications are incorporated herein by reference. While in the foregoing specification, this invention has been described in relation to certain embodiments thereof, and many details have been set forth for purposes of illustration, it will be apparent to those skilled in the art that the invention is susceptible to additional embodiments and that certain of the details herein may be varied considerably without departing from the basic principles of the invention.